Immunobiology 220 (2015) 215226

Contents lists available at ScienceDirect

Immunobiology
journal homepage: www.elsevier.com/locate/imbio

Review

Insights how monocytes and dendritic cells contribute and regulate

immune defense against microbial pathogens
Kristin Bieber, Stella E. Autenrieth
Department of Internal Medicine II, University of Tbingen, Germany

a r t i c l e i n f o a b s t r a c t

Article history: The immune system protects from infections primarily by detecting and eliminating invading pathogens.
Received 1 May 2014 Beside neutrophils, monocytes and dendritic cells (DCs) have been recently identied as important sen-
Received in revised form 17 October 2014 tinels and effectors in combating microbial pathogens. In the steady state mononuclear phagocytes like
Accepted 23 October 2014
monocytes and DCs patrol the blood and the tissues. Mammalian monocytes contribute to antimicro-
Available online 31 October 2014
bial defense by supplying tissues with macrophage and DC precursors. DCs recognize pathogens and are
essential in presenting antigens to initiate antigen-specic adaptive immune responses, thereby bridging
Keywords:
the innate and adaptive immune systems. Both, monocytes and DCs play distinct roles in the shaping of
Monocytes
Dendritic cells
immune response. In this review we will focus on the contributions of monocytes and lymphoid organ
Microbial infection DCs to immune defense against microbial pathogens in the mouse and their dynamic regulation from
Inammatory DCs steady state to infection.
Inammatory monocytes 2014 Elsevier GmbH. All rights reserved.
Tip-DCs
Innate immunity

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Development of monocytes and DCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Classical DCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
DCs as inducers of adaptive immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
DCs as tolerogenic cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Murine monocyte subsets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Role of classical DCs during microbial infection in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Bacterial transport/dissemination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Priming of NK cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Antimicrobial activity of DCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Priming of T-cell responses via maturation and cytokine secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Evasion strategies of bacterial pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Roles of CD115+ Ly6Chi inammatory monocytes/DCs and Tip-DCs during microbial infection in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Listeria monocytogenes (Lm) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Mobilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Corresponding author at: Department of Internal Medicine II, University of Tbingen, Otfried-Mller-Str. 10, D-72076 Tbingen, Germany. Tel.: +49 7071 2983156;
fax: +49 7071 294822.
E-mail address: Stella.Autenrieth@med.uni-tuebingen.de (S.E. Autenrieth).

http://dx.doi.org/10.1016/j.imbio.2014.10.025
0171-2985/ 2014 Elsevier GmbH. All rights reserved.
216 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226

Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Monopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Other infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Infection induced myelopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
Conict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Introduction (Banchereau and Steinman, 1998). DCs present tissue-derived anti-

gens to CD8+ T cells (cross-presentation) and CD4+ T cells (direct
The mammalian immune system acts against common and presentation). This leads to the induction of peripheral tolerance in
rare microbial pathogens and prevents their invasion by consti- the steady state or to effector immunity by priming of CD4+ T cells
tutive innate immune barriers in mucosal and epithelial tissues. to either T helper 1 (Th1) cells, Th2, Th17 cells, or regulatory T cells
Highly virulent pathogens, which are generally less prevalent, have (Adams et al., 2005; Mellman and Steinman, 2001; Steinman et al.,
evolved mechanisms to circumvent constitutive immune defense 2002; Steinman and Banchereau, 2007).
mechanisms. Infection with these organisms leads to the induc- Monocytes are located at the site of antigen entry and of T-
tion of auxiliary innate defenses like the activation of the cellular cell priming. They are equipped with a large range of pattern
mediators neutrophils, macrophages, and dendritic cells (DCs) to recognition receptors such as toll-like receptors (TLRs), thereby
combat the pathogen. These phagocytes internalize and digest recognizing e.g., microorganisms and subsequently producing
bacteria, infected or dying cells and produce inammatory medi- inammatory molecules. One important function of monocytes
ators thereby killing pathogens and contributing to the activation is their contribution to the renewal of DCs and some tis-
of other cell types. Thus, while granulocytes have long been known sue macrophages predominantly under inammatory conditions
as important components of anti-microbial host defense, DCs and (Geissmann et al., 2003; Randolph and Furie, 1996; Serbina and
circulating monocytes are more and more implicated as essential Pamer, 2006; Varol et al., 2007). In addition to their functions in
players in defense against a range of microbial pathogens. innate immunity data have suggested that monocytes can con-
The developmental pathway of most cellular components of tribute to the polarization and expansion of lymphocytes (Auffray
the mammalian immune system including monocytes and DCs et al., 2007; Geissmann et al., 2003; Krutzik et al., 2005; Le Borgne
starts with pluripotent stem cells in the bone marrow. They et al., 2006; Len et al., 2007; Randolph et al., 1999; Serbina and
give rise to progenitors that follow a variety of differentiation Pamer, 2006; Serbina et al., 2003).
pathways to differentiate into mature cells with dened effec- Both, monocytes and DCs may play distinct roles in the shaping
tor functions. Mammalian monocytes contribute to antimicrobial of immune responses. In this review we will focus on the contrib-
defense by supplying tissues with macrophage and DC precursors utions of monocyte and lymphoid organ DCs to immune defense
(Gordon and Taylor, 2005). In terms of infection with a viru- against microbial pathogens in the mouse and their dynamic regu-
lent pathogen, however, the normal, homeostatic differentiation lation from steady state to infection.
pathway of monocytes is temporarily modied leading to the devel-
opment of a variety of effector cells with distinct antimicrobial Development of monocytes and DCs
activities from bone marrow and blood monocytes.
DCs are a heterogeneous population consisting of classical DCs Similar to all other leukocytes, monocytes and DCs originate
and plasmacytoid DCs (pDCs) with different abilities to respond to from multipotent self-renewing hematopoietic stem cells (HSCs)
external stimuli and activate distinct effector lymphocytes (Heath residing in the bone marrow (BM) (Liu and Nussenzweig, 2010).
and Carbone, 2009; Reizis et al., 2011). They recognize and ingest During differentiation these cells give rise to multipotential pro-
pathogens and are essential in presenting antigens to initiate anti- genitor cells (MPPs), loosing sequentially self-renewal capacity
gen specic adaptive immune responses, thereby bridging the whereas their differentiation capacity becomes more restricted.
innate and adaptive immune systems (Banchereau and Steinman, MPPs further differentiate into oligopotent progenitor cells such as
1998). the common myeloid progenitor cells (CMPs) (Akashi et al., 2000)
DCs in their immature state are sentinels of the immune system giving rise to monocytes, macrophages, granulocytes, megakary-
as they patrol in the periphery and continuously take up different ocytes, and erythrocytes; and the common lymphoid progenitors
kinds of self and foreign antigens, e.g., commensals, food antigens, (CLP) forming T, B and natural killer cells (Kondo et al., 1997).
or exogenous antigens and migrate in a CCR7-dependent man- The origin of DCs in this representation of myelopoiesis and
ner to the draining lymph nodes. Following uptake, antigens are lymhpopoiesis is controversially discussed. In vitro and in vivo
processed and loaded in form of peptides on major histocompati- differentiation assays showed that CLPs are more potent at pro-
bility complexes (MHC) (Mellman and Steinman, 2001). Activation ducing thymic DCs whereas CMPs are more efcient at generation
of DCs is induced, e.g., by microorganisms, infected cells as well as of splenic and lymph node cDCs (Izon et al., 2001; Liu and
by apoptotic bodies from dying cells. After stimulation immature Nussenzweig, 2010; Manz et al., 2001; Wu et al., 2001). However,
DCs transform into mature DCs, which comprise exceptional capac- as the steady state abundance of CMPs is 10-fold higher than that of
ity for T-cell stimulation. This activation-induced transformation is CLPs, most splenic DCs and a substantial fraction of thymic DCs orig-
accompanied by a dramatic cytoplasmic reorganization leading to inate from CMPs (K. Liu and Nussenzweig, 2010). Thus, DCs share
increased expression of surface MHC class II and co-stimulatory in part the developmental pathway with monocytes, macrophages
molecules. The role of DCs is absolutely critical for the induc- and neutrophils (Fig. 1). Further studies have identied a monocyte
tion and regulation of T-cell responses (Banchereau and Steinman, and DC progenitor (MDP) (Fogg, 2006; Varol et al., 2007) giving
1998). For example T-cell activation in a mixed lymphocyte reac- rise to either monocytes or to common DC progenitors (CDPs) (Liu
tion is normally carried out with equal numbers of stimulators and et al., 2009; Onai et al., 2007b) as committed DC progenitor in the
responders, but only one DC is necessary to turn on 1003000 T cells steady state. Very recently clonal studies on a single cell level argue
 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226 217

Fig. 1. Schematic overview of the developmental pathway of DCs and monocytes in the steady state. DCs and monocytes develop from MPPs via CMP to MDP. MDPs give rise
to both monocytes and DCs via CDPs and pre-DCs. Preformed monocytes and pre-DCs migrate to the periphery where they differentiate into macrophages or DCs, respectively.
These processes are regulated by various growth factors, cytokines and transcription factors (gray). MPP: multipotential progenitor cells; CMP: common myeloid progenitor;
MDP: monocyte & DC progenitor; pre-DC: precursor of DCs, pDC: plasmacytoid DC, mono: monocyte, MF: macrophage.

against the MDP as a homogenous progenitor of both monocytes
and DCs (Sathe et al., 2014). Therefore, it is highly debated by the
community whether MDPs are an intermediate progenitor of DCs.
CDPs have lost their potential to differentiate into monocytes or
macrophages and exclusively give rise to pDCs and to committed
precursor of cDCs, the pre-cDCs (Gordon and Taylor, 2005; Liu et al.,
2009; Naik et al., 2007; Onai et al., 2007a). While MDPs and CDPs
are restricted to the BM, pre-cDCs migrate from the BM through
the blood to peripheral lymphoid and non-lymphoid organs, where
they further differentiate into DCs (Ginhoux et al., 2009; Heath
and Carbone, 2009; Liu et al., 2009; Reizis et al., 2011). Human
monocytes cultured with GM-CSF and IL-4 differentiate into DCs
in vitro (Banchereau and Steinman, 1998; Palucka, 1998; Sallusto
and Lanzavecchia, 1994). In humans, however, it has never been
shown that monocytes can give rise to DCs in situ.
This led to the hypothesis that monocytes are the immediate
upstream precursors of DCs. However, further in vivo studies in
the mouse revealed that monocytes give mainly rise to DCs under
inammatory and infectious conditions leading to the adopted
concept of monocytes as precursors of inammatory DCs such
as monocyte-derived DCs (mo-DCs) (Len et al., 2007; Mellman
and Steinman, 2001; Randolph et al., 1999; Varol et al., 2007) and
Tip-DCs (TNF--iNOS-producing DCs) (Banchereau and Steinman,
1998; Naik et al., 2006; Serbina et al., 2003). It should be stressed
that Tip-DCs neither constitute a separate DC lineage nor a DC
subtype, but simply represent an activation status. Every type of
myeloid DC can be activated for the expression of inducible NO
synthase (iNOS) and TNF- by microbial and cytokine stimuli.
DC differentiation in the steady state is mostly driven by FMS-
related tyrosine kinase 3 ligand (Flt3L) with contribution of other
growth factors like GM-CSF. Flt3L is required for the DC commit-
ment of early hematopoietic progenitors in the BM (Banchereau
and Steinman, 1998; Mackarehtschian et al., 1995) and likewise
for the nal steps of homeostatic DC differentiation in periph-
eral organs in vivo (Adams et al., 2005; Mellman and Steinman,
2001; Steinman, 2002; Steinman and Banchereau, 2007; Waskow
et al., 2008). GM-CSF (Csf-2) seemed to be involved in the develop-
ment of inammatory DCs (Geissmann et al., 2003; Randolph and
Furie, 1996; Schmid et al., 2010; Serbina and Pamer, 2006; Varol
et al., 2007) and the regulation of non-lymphoid tissue-resident
DCs (Auffray et al., 2007; Geissmann et al., 2003; Greter et al.,
2012; Krutzik et al., 2005; Le Borgne et al., 2006; Len et al., 2007;
Randolph et al., 1999; Serbina et al., 2003; Serbina and Pamer,
2006), but leaves the homeostasis of steady-state DCs unaltered.
However, recent ndings using Csf2rb/ Csf2rb2/ mice argue
against an involvement of GM-CSF in the differentiation of inam-
matory DCs, instead this study revealed M-CSF al the master driver
for inammatory DC development in different infection models
(Greter et al., 2012).
Blood monocyte development is dependent on the growth factor
M-CSF (Csf-1) and its receptor (Cecchini et al., 1994; Dai et al., 2002;
Liu and Nussenzweig, 2010), whereas GM-CSF and Flt3L appear to
be dispensable for monocyte development.
Furthermore, commitment and differentiation to DCs and
monocytes of BM progenitors is tightly orchestrated by the expres-
sion and balance of different transcription factors (Akashi et al.,
2000; Belz and Nutt, 2012; Miller et al., 2012). A number of
transcription factors have been shown to be involved in the devel-
opment of DCs and DC subsets like PU.1, ID2, Zbtb46, BatF3,
interferon regulatory factors (IRFs) and STATs (see review (Kondo
et al., 1997; Merad et al., 2013), whereas transcription factors like
PU.1, MafB, c-Maf and KLF-4 are required for monocyte differenti-
ation (Auffray et al., 2009b; Izon et al., 2001; Liu and Nussenzweig,
2010; Manz et al., 2001; Wu et al., 2001). By antagonistic interaction
with different transcription factors PU.1 controls several cell fate
decisions along the myeloid pathway. Thus, the relative expression
levels and the balance of transcription factors are important. For
example, the expression of PU.1 in MDPs is essential for DC differen-
tiation, whereas ectopically expressed MafB induces differentiation
into monocytes and macrophages thereby inhibiting DC commit-
ment (Bakri, 2005; Carotta et al., 2010; Liu and Nussenzweig, 2010).
Classical DCs
Classical DCs (here referred to as DCs) are the main DC subset
in the lymphoid organs of mice and can be further differenti-
ated by their surface marker expression and location. As recently
reviewed by Merad et al. DCs are located in lymphoid tissues
where they are termed CD8+ DCs and phenotypically described as
CD11c+ CD11b CD8+ MHCII+ B220 or CD11b+ DCs, which express
218 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
CD11c+ CD11b+ CD8 MHCII+ B220 on their cell surface (Fogg,
2006; Merad et al., 2013; Varol et al., 2007; Vremec et al., 2000). In
non-lymphoid tissues DCs are divided by their distinct expression
of the surface markers CD11b and CD103 into CD103+ CD11b DCs,
CD103+ CD11b+ intestinal DCs and CD103 CD11b+ DCs (Liu et al.,
2009; Merad et al., 2013; Onai et al., 2007b). Beside these tissue DCs,
Langerhans Cells (LC), which are located in the epidermal layer of
the skin and are characterized by the high level expression of the
C-type lectin Langerin (CD207) form another subset of DCs (Merad
et al., 2008; Sathe et al., 2014).
DCs as inducers of adaptive immunity
In the steady state DCs are enriched at the borderlines of the
body with the environment like the gut, lung, skin, the marginal
zone in the spleen or the subcapsular sinus in the lymph nodes (LN)
and are functionally specialized to sense pathogens (Helft et al.,
2010; Idoyaga et al., 2009). DCs express a specic set of pattern
recognition receptors to sense bacteria, viruses, fungi, parasites as
well as dead cells and necrotic bodies (Cambi et al., 2003; Davey
et al., 2010; Edwards et al., 2003; Sancho et al., 2009; Yarovinsky,
2005). Activation of DCs drives immature cells to migrate in
response to chemokines into lymph nodes or the spleen where they
develop into a mature phenotype. The maturation process is accom-
panied by the disappearance of the antigen-capturing apparatus
and the up-regulation of essential co-stimulatory molecules such as
CD80, CD86 and CD54. In addition maturation leads to an increased
display of MHC molecules with antigenic peptides on the cell sur-
face (Banchereau and Steinman, 1998). Antigen presentation by
DCs displays a critical process, as T cells will ignore unhandled anti-
gens. CD8+ DCs are critical for the induction of anti-viral CD8+
T-cell responses in vivo due to their cross-presentation potential
as well as production of IL-12 and IL-15, two cytokines critical for
cytotoxic CD8+ T-cell differentiation. In contrast, CD11b+ DCs are
more efcient in MHC II-mediated CD4+ T-cell activation in the
steady state and upon bacterial infections [reviewed by (Merad
et al., 2013; Villadangos and Schnorrer, 2007)]. This is supported
by results showing that the preferential priming of CD8+ and CD4+
T cells by CD8+ and CD8 DCs, respectively, correlates with the
differential capacity of these DC subsets to process and present anti-
gens in association with MHC class I and MHC class II molecules
(Dudziak et al., 2007).
Furthermore, DCs are able to promote B-cell proliferation into
plasma cells (Dubois et al., 1998, 1997) mediated via soluble fac-
tors released by activated DCs or by direct cellcell interaction
(Obayashi et al., 2006; Wan et al., 2008).
DCs as tolerogenic cells
Beside their important role during infections DCs are involved in
the induction of tolerance. Central tolerance in the thymus is medi-
ated by negative selection of developing thymocytes or induction
of T regulatory cells (Tregs) [reviewed in (Hsieh et al., 2012; Klein
et al., 2009)]. Developing T cells that recognize self-peptides, which
are presented by thymic DCs or epithelial cells, with a sufciently
high afnity are either deleted through negative selection or dif-
ferentiate into Tregs. Injection of antigen-bearing DCs directly into
the developing thymus results in deletion of the reactive T cells
(Brocker et al., 1997). Similarly, CD8lo Sirp+ DCs in the thymus,
which are phenotypically more mature than their Sirp coun-
terparts, can induce antigen-specic Tregs (Proietto et al., 2008).
Peripheral tolerance on the other hand is mediated by DCs through
generation of Tregs and clonal deletion of self-reactive T cells. DC-
induced generation of Tregs is mainly mediated by IL-27, TGF-,
IL-10, retinoic acid, indoleamine-2,3-dioxy-genase and vitamin D.
Treg generation is either mediated by tissue resident specic DC
subsets with a specialized Treg inducing function or by the action
of the mentioned mediators present in local tissue microenviron-
ment, which act on DCs and drive them to behave as tolerogenic DCs
and induce Treg differentiation. The clonal deletion of self-reactive
T cells is mediated by the presentation of tissue-derived antigens
on MHC molecules expressed by predominantly immature DCs in
the steady state (Kushwah and Hu, 2011; Liu et al., 2002; Qiu et al.,
2009).
Murine monocyte subsets
Murine blood monocytes can be divided in two subsets. Both
subsets express CD115 (M-CSFR), CD11b, and low levels of F4/80.
One subset expresses in addition Ly6C, the chemokine receptor
CCR2, the adhesion molecule L-Selectin (CD62L) and the 7/4 anti-
gen (Henderson et al., 2003; Taylor et al., 2003). This subset of
CD115+ Ly6Chi cells is named inammatory monocytes due to their
selective recruitment to inamed tissues and lymph nodes where
they differentiate into inammatory DCs (Geissmann et al., 2003;
Palframan et al., 2001; Serbina et al., 2003; Sunderktter et al.,
2004).
The second subset of monocytes is characterized by high expres-
sion of the chemokine receptor CX3CR1, LFA-1 and CD43 but low
expression of Ly6C and no CCR2 expression (Geissmann et al., 2003;
Sunderktter et al., 2004). They are smaller in size, have a longer
half-life, and trafc into peripheral tissues under non-inammatory
conditions (Geissmann et al., 2003). They were termed resident
monocytes because they reconstitute tissue macrophages and DCs.
More recent studies revealed that the CD115+ Ly6C monocytes are
specialized in crawling in the blood vessels for extended periods of
time thereby patrolling the endothelium (Auffray et al., 2007) for
scavenging dead cells or potential pathogens. For this CD115+ Ly6C
monocytes were termed patrolling monocytes. Infection or tissue
damage leads to the rapid extravasation of CD115+ Ly6C mono-
cytes and invasion of the inamed tissue, which is hardly observed
in the steady state (Auffray et al., 2007).
Role of classical DCs during microbial infection in vivo
As already mentioned DCs hallmark outstanding functions
related to defense mechanisms against invading pathogens. There-
fore pathogens have evolved many strategies to evade such host
immune responses as provided by DCs. In this section we want
to dissect on the one hand the role of DCs during systemic infec-
tions and on the other hand the evasion-strategies of the invading
pathogen. To elucidate the role of DCs during systemic infections
in more detail and in a more physiological way in vivo studies
in mouse experimental models in combination with DC depletion
using diphtheria toxin mouse models are a common approach.
Table 1 summarizes the ndings of DC depletion in various mouse
infection models discussed in the following section (Table 1).
Bacterial transport/dissemination
Recently, subpopulations of CD11c+ DCs have been implicated
at various stages of Listeria immunity, including the transport of
blood-borne Listeria monocytogenes (Lm) to the spleen by CD8+
DCs (Neuenhahn et al., 2006; Verschoor et al., 2011) and the early
activation of CD8+ T cells (Jung et al., 2002). Lm rapidly associated
with platelets in the bloodstream, which are specically taken up
by splenic CD8+ DCs and thereby target Lm to these cells. Platelet
tagging was also observed with other Gram-positive bacteria (S.
aureus, E. fecalis, B. subtilis, S. pneumoniae (encapsulated and non-
capsulated)) suggesting a broadly active shuttling mechanism for
systemic bacteria (Verschoor et al., 2011). In the rst study of the
 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
Table 1
Summary of the outcome of DC depletion in infectious disease models.
Functional category of DCs Benecial effects of DC depletion
Pathogen transport/dissemination Lm
NK cell priming
Antimicrobial activity Y. enterocolitica
E. coli
T cell priming:
Cytokine production
Th1
Th2
CD8+ T cells
group from Bush and co-workers DC-depletion seemed to be ben-
ecial for Lm systemic infection due to reduced spreading of the
bacteria (Neuenhahn et al., 2006), but it was only clear after the
second study that targeting Lm and other bacteria to CD8+ DCs
by platelets results in the induction of anti-bacterial immunity
(Verschoor et al., 2011) and is thereby benecial for the host.
In addition, DCs are shown to be important host cells for the dis-
semination of various pathogens. For example in a mouse model of
subcutaneous Streptococcus pyogenes infection ablation of DCs led
to increased bacterial dissemination into draining lymph nodes and
systemic organs (Loof et al., 2007). Experiments with Salmonella
dublin addressed the efcient internalization, survival and repli-
cation within puried DCs. Similar to the experiments discussed
above DCs are the main subset that harbor Salmonella (Marriott
et al., 1999). Infection experiments with Mycobacterium bovis bacil-
lus CalmetteGuerin (BCG) revealed DCs as a reservoir for bacteria
as BCG bacilli survive but do not proliferate during the rst two
weeks of an infection (Jiao et al., 2002). It is still not completely
understood how these bacteria avoid intracellular killing.
Priming of NK cells
DCs are important cytokine producers in the early stages of
infections. In murine models of Lm, Staphylococcus aureus, and
Toxoplasma gondii infections DCs were the outstanding source of
IL-12 as an antimicrobial molecule (Liu et al., 2006; Schindler et al.,
2012; Tam and Wick, 2006). IL-12 produced upon Listeria infec-
tion stimulates natural killer (NK)-cell activity, including IFN-
production, which in turn further activates macrophages, DCs and
neutrophils (Tripp et al., 1993). Activation of splenic DCs by Listeria
induced rapid clustering of innate cells, including granulocytes, NK
cells, and monocytes, to sites of bacterial localization (Kang et al.,
2008). Herein, DC-depletion completely abrogated the infection-
induced clustering of these incoming innate immune cells and the
production of IFN- by NK cells, which in turn prevented the dif-
ferentiation of Tip-DCs from monocytes. Thus, spatial organization
of the early immune response by DCs ensures functional activation
of innate cells. In line with these studies ablation of DCs revealed
that the in vivo priming of NK cell responses to TLR ligands, viruses
like vaccinia, LCMV, and HSV-1, the bacterial pathogen Lm and the
parasite Leishmania infantum required the presence of classical DCs
for optimal IFN- production (Hochweller et al., 2008; Kassim et al.,
2009; Lucas et al., 2007; Schleicher et al., 2007). IL-15 produced by
DCs, that is induced by type I IFNs after TLR stimulation, was neces-
sary and sufcient for the priming of NK cells in the Listeria infection
219
Detrimental effects of DC depletion Refs.
Neuenhahn
Lm, S. aureus, E. fecalis, B. subtilis, S. pneumoniae Verschoor
S. pyogenes Loof
Leishmania infantum Schleicher
Lm, vaccinia, LCMV Lucas
HSV-1 Kassim
Autenrieth
Tittel
S. aureus Schindler
S. thyphimurium Salazar-Gonzales
M. tuberculosis Tian, Samstein
Schistosoma mansonii Phythian-Adams
Inuenza Belz
VSV Ciavarra
LCMV, MHV Probst, Birnberg
Lm Jung
Plasmodium yoelii Jung
model (Lucas et al., 2007), whereas in the visceral Leishmania model
TLR9 signaling by DCs and their subsequent production of IL-12 led
to NK cell priming (Schleicher et al., 2007). These studies demon-
strate that depletion of DCs is detrimental for NK cells priming
and point out the importance of DC/NK cell interactions and the
help of DCs to induce antimicrobial NK cell responses in secondary
lymphoid organs.
Antimicrobial activity of DCs
Antimicrobial DC functions can be replaced or taken over by
other immune cells. Two independent studies showed, that the
depletion of DCs leads to the inux of phagocytes, namely neu-
trophils and monocytes, to the spleen or the kidney (similar to
Kang et al. (Kang et al., 2008)). Infection of these mice with Yersinia
enterocolitica results in an increased survival rate and signicantly
lower bacterial load due to the increased numbers of phagocytes in
the spleen as well as their enhanced anti-bacterial killing capacity
dedicated to additional ROS (reactive oxygen species) production
(Autenrieth et al., 2012). Similar observations were made by Tit-
tel et al. showing that DC-depletion induced neutrophilia leading
to reduced bacterial load in the kidney in a pyelonephritis model
(Tittel et al., 2012). In case of antimicrobial activity as rst line of
defense against invading pathogens DC depletion is benecial as it
leads to the accumulation of more effective phagocytes at the site
of infection.
Priming of T-cell responses via maturation and cytokine secretion
Most bacterial infections induce the maturation of DCs, which
is a prerequisite for T-cell activation (Autenrieth et al., 2010;
De Trez et al., 2005; Flohe, 2005; Sponaas, 2006; Sundquist and
Wick, 2005; Tam and Wick, 2006, 2004). In Salmonella-infected
mice, maturation is induced directly in DCs associated with intra-
cellular Salmonella and indirectly via Salmonella-induced TNF
production (Sundquist and Wick, 2005). Infection experiments
with the extracellular Gram-negative bacterium Yersinia entero-
colitica highlighted that pathogens differentially affect subsets
of DCs. In contrast to Salmonella infection, Y. enterocolitica dif-
ferently affect the maturation of splenic DC subpopulations and
injection of pathogenicity factors into splenic DCs, predominantly
into CD8+ DCs, diminished the up-regulation of MHC II and co-
stimulatory molecules. Indeed, only a small fraction of DCs is
infected in vivo. It will be interesting to identify the factors responsi-
ble for this cell tropism. These can be receptors especially expressed
220 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
by CD8+ DCs, e.g., CD205, or the localization in the tissues. Y.
enterocolitica impaired the antigen uptake and degradation capac-
ity as well as cytokine production of CD8+ DCs but not CD11b+
DCs (Autenrieth et al., 2010). Consequently, a reduced CD4+ T-
cell proliferation was observed in Yersinia-infected mice, and a
proper CD4+ T-cell response is necessary for the eradication of
the pathogen (Autenrieth et al., 1992, 2010), demonstrating that
microbial pathogens have successfully evolved strategies to com-
bat DC functions. Ex vivo studies revealed, that CD8+ DCs from
infected mice were mostly impaired in their T-cell activation capac-
ity, suggesting that direct infection of DCs is necessary for effective
modulation of DC functions (Autenrieth et al., 2010). Studies from
a polymicrobial sepsis model (CLP) revealed that splenic DCs from
septic mice released high levels of IL-10 compared to DCs from
control mice, whereas they were unable to secrete IL-12, even upon
stimulation with TLR ligands. These DC revealed a reduced capacity
for allogeneic T-cell activation that was associated with decreased
IL-2 production (Flohe, 2005). It would be interesting to know as to
whether DCs acquire a tolerogenic phenotype by IL-10 production
leading to the induction of Tregs in this model thereby modulating
T-cell activation.
In contrast to these studies, fully functional DCs are rapidly
recruited into infected tissue in a systemic infection model with
S. aureus. DC-depletion revealed a benecial effect afforded by DCs
during S. aureus infection, which was not mediated by their con-
tribution to direct bacterial killing, nor by increased neutrophil
recruitment, but rather by their IL-12 production (Schindler et al.,
2012), thereby most likely promoting T- and NK cell priming. In this
direction, ablation of DCs abolished IL-12 production in a Strepto-
coccus pyogenes model, which is required for effective control of
infection (Loof et al., 2007).
Using DC depletion it was shown that DCs have an outstand-
ing ability to induce T-cell priming in various infection disease
models. As already mentioned, DCs are essential to induce an effec-
tive long term CD8+ T cell mediated protective immunity upon
infection with living but not killed Lm (Jung et al., 2002; Muraille
et al., 2005) and in various virus infection models (Belz et al.,
2007; Birnberg et al., 2008; Ciavarra et al., 2005; Probst and van
den Broek, 2005). In addition to CD8+ T-cell response, DCs are
essential for CD4+ T-cell priming. For example, Salazar-Gonzales
and colleagues showed that a specic CCR6+ DC subset mediates
pathogen-specic activation of CD4+ T cells in Peyers Patches upon
oral infection with Salmonella typhimurium (Salazar-Gonzalez et al.,
2006). Using a murine Mycobacterium tuberculosis model it was
shown that even though monocyte-derived DCs deliver M. tuber-
culosis from the lung to lymph nodes (Samstein et al., 2013) and
acquire a DC-like phenotype, classical DCs induce proliferation of
M. tuberculosis-specic CD4+ T cells (Samstein et al., 2013; Tian
et al., 2005). DCs were also shown to be critical for the induction
and development of Th2 response in a mouse infection model with
the parasitic helminth Schistosoma mansoni (Phythian-Adams et al.,
2010).
All these studies clearly provide evidence for the importance
of DCs in T-cell activation in various infection models and that DC
depletion is detrimental for the outcome of infections. Although DC
depletion is at least in the beginning of an infection benecial for
the innate anti-microbial response against bacterial pathogens by
modulating phagocyte homeostasis and activity, all the data on NK
cell- and T-cell priming argue for an essential role of DCs for the
induction of adaptive immunity, which is shown to be necessary to
overcome systemic infections.
Evasion strategies of bacterial pathogens
One prominent immune evasion strategy of microbial
pathogens is the induction of cell death of DCs. Following infection
with Y. enterocolitica the numbers of splenic CD4+ and CD8+ DCs
are reduced partly due to TLR4-dependent induction of cell death
(Autenrieth et al., 2010). Similarly, infection of mice with E. coli or
treatment with LPS led to markedly reduced numbers of CD4+ and
CD8+ DCs, a result of TLR4-TRIF signaling induced apoptosis (De
Smedt et al., 1996; De Trez et al., 2005). Furthermore, oral infection
of mice with Salmonella typhimurium specically induces death of
CD8+ DCs, but not of CD8 DCs, via MyD88 and TNFR1 signaling
(Sundquist and Wick, 2009). A signicant loss of DCs during a
systemic infection was also shown in a model of cecal ligation and
puncture (CLP)-induced polymicrobial sepsis, which was depend-
ent on TLR2 and TLR4 signaling (Efron et al., 2004; Pne et al.,
2009). Similar ndings were observed in the human system: in
sepsis patients the number of splenic DCs is dramatically reduced,
whereas the number of macrophages is not affected (Hotchkiss
et al., 2002). These ndings resemble them from the conditional DC
depletion studies described above and it is tempting to speculate
that the more pronounced the reduction of DCs at the onset of an
infection is and the longer the DC numbers are reduced the worse
the course of infection will be. As a number of bacterial infections
lead to reduced DC numbers the question arises whether the host
has developed alternative strategies to overcome this evasion
mechanism.
Roles of CD115+ Ly6Chi inammatory monocytes/DCs and
Tip-DCs during microbial infection in vivo
Describing the role of monocytes during microbial infections
we are going to focus on the CD115+ Ly6Chi inammatory mono-
cyte subset. This is due to the fact that there is barely any
report describing an important function of CD115+ Ly6C/low res-
ident monocytes upon infection. At least Auffray et al. showed
that resident CD115+ Ly6Clow monocytes can be recruited to
sites of infection and thereby contribute to the initial inam-
matory response, e.g., by the release of TNF (Auffray et al.,
2007).
Upon infection monocytes are rapidly recruited to the site
of inammation (Geissmann et al., 2003; Randolph et al., 1999;
Sunderktter et al., 2004) and in such situations they can out-
number DCs and macrophages. Ly6Chi monocyte-derived cells have
been classied on the basis of a set of restricted but non-exclusive
functional properties as monocyte-derived DCs or inammatory
DCs, monocyte-derived macrophages or myeloid-derived suppres-
sor cells (MDSCs). However, it lacks suitable methods to exactly
discriminate between different populations of these monocyte-
derived cells. Due to this, it was recently suggested to term these
cells monocyte-derived cells or short MCs with distinct prop-
erties, e.g., iNOS+ MCs for Tip-DCs (Guilliams et al., 2014). In
the following section we refer to the MCs and their function
upon microbial infection like there were described in the original
papers.
Monocytes are able to take up antigens in peripheral tis-
sues and in the course of inammation, transport them to
the draining lymph nodes. In addition, they produce cytokines
and inammatory or antiinammatory mediators, and dif-
ferentiate into antigen-presenting cells (inammatory DCs)
(Geissmann et al., 2003; Randolph et al., 1999). Inamma-
tory DCs are dened by their expression of CD11c+ CD11b+ MHC
II+ F4/80+ Ly6C+ CD206+ CD115+ CD64+ FcRI+ , their absence in the
steady state, their migration from tissues to lymph nodes and their
ability to activate T cells (Segura and Amigorena, 2013). The best
markers used to discriminate macrophages from inammatory DCs
are CD64 and FcRI. Tip-DCs are a subset of inammatory DCs
initially identied in a Lm mouse infection model due to their pro-
duction of TNF- and iNOS.
 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
Listeria monocytogenes (Lm)
Several studies have characterized the role of monocytes
in vivo following microbial infection of mice with the intracellu-
lar bacterium Lm (Serbina et al., 2003; Serbina and Pamer, 2006;
Sunderktter et al., 2004). Lm infection leads to a massive CCR2-
dependent egress of Ly6Chi monocytes from bone marrow to the
bloodstream. The maximum recruitment of monocytes occurs 72
to 96 h following infection and thus is delayed relative to gran-
ulocyte recruitment (North, 1970). At the site of infection Ly6Chi
monocytes differentiate in a MyD88-dependent manner into called
Tip-DCs producing TNF- and iNOS combined with up-regulation
of MHC II, CD80, CD86, and CD11c on the cell surface (Serbina et al.,
2003; Serbina and Pamer, 2006; Tsou et al., 2007). TLR-signaling
is required for protection during Lm infection, and mice decient
in the TLR adaptor molecule, MyD88, are highly susceptible to
infection due to diminished IL-12, IFN-, TNF- and NO responses
(Edelson, 2002; Seki et al., 2002).
Mobilization
CCR2-decient mice have reduced numbers of Tip-DCs, which
is associated with impaired control and clearance of Lm following
infection (Serbina et al., 2003). Lm infection leads to the produc-
tion of MCP-1 (CCL2) with detectable levels in spleen 6 h after
bacterial inoculation (Kurihara et al., 1997; Serbina et al., 2003),
Following Lm infection MCP-1 is produced in two phases. The
rst TLR/MyD88 signaling-dependent phase is rapid and induces
low-levels of MCP-1, whereas the second IFNR-dependent phase
promotes prolonged and higher levels of MCP-1 secretion (Jia et al.,
2009). Recently, at least one source of MCP-1 was identied. Low
concentrations of TLR ligands in the bloodstream induce the pro-
duction of MCP-1 by bone marrow mesenchymal stem cells (MSCs)
and their progeny, including CXC chemokine ligand (CXCL)12-
abundant reticular (CAR) cells leading to the CCR2-dependent
emigration of monocytes from the bone marrow (Shi et al., 2011). In
addition to TLR- and IFNAR-signaling MPYS, a four-transmembrane
protein essential for Lm induced type I IFN production in vitro
(Ishikawa and Barber, 2008) was identied as player in the induc-
tion of monocyte emigration from the bone marrow following Lm
infection. MPYS mediates type I IFN production by sensing cytosolic
bacterial DNA (Ishikawa et al., 2009). Infection of MPYS decient
mice with Lm lead to increased bacterial burden in the liver, which
correlated with the diminished production of MCP-1 and reduced
Ly6C+ monocyte frequencies in blood and liver (Jin et al., 2013).
Antimicrobial activity
Tip-DCs were not directly infected with Lm and therefore are
probably not involved in bacterial transport to the spleen (Serbina
et al., 2003). Mice with a genetic deciency in iNOS, gp91, or
p47phox or mice treated with the iNOS inhibitor aminoguani-
dine are more susceptible to Lm infection (Beckerman et al., 1993;
Dinauer et al., 1997; Endres et al., 1997), implicating an inu-
ence of these mechanisms in bacterial clearance. Tip-DCs are not
essential for T-cell priming in vivo, although they are able to ef-
ciently stimulate mixed lymphocyte reactions in vitro, as CD8 and
CD4 T-cell responses to Lm are preserved in CCR2-decient mice
(Serbina et al., 2003). These ndings suggest that the main role
of these cells is to combat the pathogen by killing rather by reg-
ulating T-cell responses although they may inuence the latter
by their extraordinary production of the inammatory mediator
TNF-. Mice with a selective depletion of TNF- in monocytes
and macrophages are highly susceptible to Lm infection, suggest-
ing that these cell populations are the relevant source of TNF- in
defense against Lm infection (Grivennikov et al., 2005). Although
221
CX3CR1 is only weakly expressed by Ly6Chi monocytes deciency
of CX3CR1 impaired the recruitment of these Tip-DC precursors
to the spleen during acute Lm infection and decreased the ef-
ciency of bacterial clearance (Auffray et al., 2009a). Recently, IL-23
was shown to be required for the optimal recruitment of Tip-
DCs. Lm-infected IL-23p19 KO mice revealed reduced levels of the
monocyte-recruiting chemokines CCL2 and CCL7 and in conse-
quence fewer monocytes in the spleen. Additionally, the overall
concentrations of TNF- and nitric oxide as well as numbers of
Tip-DCs were reduced in IL-23p19 KO mice leading to increased
bacterial burdens in the spleen upon Lm infection (Indramohan
et al., 2012). Thus, Ly6Chi monocytes/Tip-DCs are essential in medi-
ating innate anti-microbial host defense upon Lm infection in vivo.
Monopoiesis
In addition to monocyte egress and differentiation of monocytes
into Tip-DCs Lm infection specically and selectively promotes
monopoiesis accompanied by marked proliferation of bone mar-
row monocyte precursors and the depletion of myeloid progenitors
already 2 days post infection. The replenishment of monocytes
depends on MyD88/Trif signaling whereas it is dispensable for early
emigration of the mature monocytes from the bone marrow. Thus,
TLR-mediated signals are essential for the maintenance of mono-
cyte homeostasis during systemic bacterial infection (Serbina et al.,
2009).
Infection of mice with very high bacterial dose has been used to
investigate the pathogenesis of Lm meningitis. In these settings, Lm
is found predominantly in circulating Ly6C+ inammatory mono-
cytes in the bloodstream and bone marrow (Drevets, 1999; Drevets
et al., 2004; Join-Lambert et al., 2004; Sunderktter et al., 2004). Fol-
lowing infection Lm-infected Ly6C+ monocytes are recruited into
the brain parenchyma independently of bacterial invasion of the
CNS. This recruitment is triggered by proinammatory cytokines,
in particular IFN-, produced by the innate immune response to
intracellular infection in peripheral organs (Drevets et al., 2010a,
2008). These data indicate that despite the abundant presence of
IFN- and TNF- BM monocytes developing during lethal infec-
tion fail to acquire bactericidal activity. Further studies revealed
that BM monocytes phagocytose Lm only in lethal infection yet
they have increased antiinammatory signaling pathways, mak-
ing these cells unresponsive to proinammatory stimuli that could
trigger bactericidal activity (Drevets et al., 2010b).
Other infections
The importance of inammatory Ly6Chi monocytes/Tip-DCs
have also been reported in other infectious models in vivo and in
which they contribute to the control of pathogen growth during
infections with bacteria, such as Mycobacterium tuberculosis (Peters
et al., 2001; Scott and Flynn, 2002), Brucella melitensis (Copin et al.,
2007, 2012), Burkholderia mallei (Goodyear et al., 2010), or with
parasites, such as Plasmodium chabaudi (Sponaas et al., 2009), Toxo-
plasma (Courret, 2006; Robben, 2005) and Leishmania major (De
Trez et al., 2009; Len et al., 2007).
In contrast to these benecial effects of inammatory Ly6Chi
monocytes/Tip-DCs there are also microbial infections in which
these cells are suppressed or even pathological. During a model
of septic peritonitis neutrophils suppress peritoneal functions of
Tip-DCs through the production of IL-10 (Ocuin et al., 2011). More-
over, Trypanosoma brucei infection led to the accumulation of
Tip-DCs in the spleen, liver, and lymph nodes, which contribute
actively to tissue damage during the chronic stage of T. brucei infec-
tion due to their sustained production of high amounts of TNF
and iNOS (Guilliams et al., 2009). This infection-induced Tip-DC
222 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
Fig. 2. Modulation of myelopoiesis by infection. The inuence of the various infection agents on the developmental pathway of DCs and monocytes are summarized in here.
Infections induce TLR-dependent (i) DC depletion in the periphery, (ii) biased TLR- and IFN--dependent promotion of monopoiesis, and (iii) differentiation of monocytes to
Tip-DCs.
development is regulated by IL-10 and dependent on CCL2/CCR2,
IFN- and MyD88 signaling (Bosschaerts et al., 2010; Guilliams
et al., 2009). Similarly, in a systemic Candida infection model
type I interferons were shown to promote fatal immunopathol-
ogy by regulating inammatory monocytes and neutrophils
(Majer et al., 2012). The high presence and activity of Tip-DC
s and neutrophils in the kidney during the early phase of Can-
dida infection promotes a secondary strong inux of neutrophils
culminating in lethal immunopathology.
Recently cells similar to the Tip-DCs were described that provide
protection against a secondary Lm infection, suggesting that these
cells may be important for primary and secondary protective
immunity (Narni-Mancinelli et al., 2007).
In addition to the ndings that NO produced by Tip-DCs directly
control their pathogen burden a study by Olekhnovitch et al.
argues for a collective nitric oxide production by numerous phago-
cytes providing tissue-wide immunity during Leishmania infection
proposing the model of a cooperative mechanism that generates
an antimicrobial milieu providing the basis for pathogen control at
the tissue level (Olekhnovitch et al., 2014).
Infection induced myelopoiesis
Several studies described the induction of monopoiesis by
microbial pathogens or pathogen derived molecules (Baldridge
et al., 2011; Belyaev et al., 2013; de Bruin et al., 2012; MacNamara
et al., 2011; Murray et al., 1998; Nagai et al., 2006; Serbina
et al., 2009; Ynez et al., 2011) (Fig. 2). Pathogen induced alter-
ation of hematopoiesis may involve direct action on hematopoietic
stem and progenitor cells, as they express TLRs and myeloid cells
could be generated from HSPCs by direct stimulation with LPS
via TLR4- and MyD88-dependent signaling in vitro (Nagai et al.,
2006; Schmid et al., 2011). This is in contrast to ndings by
Boettcher et al. showing a key and nonredundant role for the
nonhematopoietic cell compartment in pathogen sensing, which
is subsequently translated into cytokine release for enhanced,
demand-adapted myeloid cell production (Boettcher et al., 2012).
Several studies demonstrate the requirement of innate immune
sensing for myelopoiesis. TLR2-MyD88 signaling is essential for
the production of myeloid cells in mice infected with Candida
albicans (Ynez et al., 2011, 2009), whereas the maintenance of
monocytes during Lm infection (Serbina et al., 2009) requires
MyD88 signaling. Thus, the host responds to a wide variety of
pathogens by the infection-induced modication of hematopoiesis
via TLR- and MyD88-mediated signaling. Alternatively, induction
of monopoiesis may result from circulating bacterial products or
from mediators produced by other cells in response to TLR activa-
tion. Recently, it became obvious that IFN- mediated signals are
also essential for functional myelopoiesis upon infection with var-
ious pathogens, e.g., Ehrlichia, lymphocytic choriomeningitis virus
(LCMV), and Plasmodium chabaudi (Belyaev et al., 2013; de Bruin
et al., 2012; Goldszmid et al., 2012; MacNamara et al., 2011).
Concluding remarks
The immune system protects from infections primarily by
detecting and eliminating the invading pathogens. Beside neu-
trophils, monocytes and DCs have been recently identied
as important sentinels and effectors in combating microbial
pathogens. In the steady state mononuclear phagocytes like mono-
cytes and DCs patrol the blood and the tissues. During microbial
infections there is a need of monocytes and DCs with specic
functions to elicit the appropriate immune response against the
invading pathogens. The variety of diverse subtypes of monocytes
and DCs with different functions during the steady state and upon
infections is amazing and it possibly reects the variety of differ-
ent microbial pathogens, different compartments and tissues, as
well as different biological cell features like life span. The optimal
 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
immune response is determined by the balance between efcient
pathogen clearance and an acceptable level of immunopathology
elicited by the immune response. Further insights into the com-
plex mutual regulation of microbial pathogens and the immune
system are needed. While the initiation of inammatory processes
and myeloid cell development has been studied in detail in the
past years, the mechanisms that down-regulate these events are
less well understood.
Conict of interests
The authors declare no conicts of interests.
Acknowledgement
The authors would like to thank Ingo B. Autenrieth and Man-
ina Gnter for critical reading of the manuscript. The work was
supported by the Deutsche Forschungsgemeinschaft (AU338/3-1,
SFB 685 (TP-A3), SFB654 (TP-C7)) and the European Social Fund in
Baden-Wrttemberg.
References
Adams, S., ONeill, D.W., Bhardwaj, N., 2005. Recent advances in dendritic cell biol-
ogy. J. Clin. Immunol. 25, 8798, http://dx.doi.org/10.1007/s10875-005-2814-2.
Akashi, K., Traver, D., Miyamoto, T., Weissman, I.L., 2000. A clonogenic common
myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193197,
http://dx.doi.org/10.1038/35004599.
Auffray, C., Fogg, D., Garfa, M., Elain, G., Join-Lambert, O., Kayal, S., Sarnacki, S.,
Cumano, A., Lauvau, G., Geissmann, F., 2007. Monitoring of blood vessels and
tissues by a population of monocytes with patrolling behavior. Science 317,
666670, http://dx.doi.org/10.1126/science.1142883.
Auffray, C., Fogg, D.K., Narni-Mancinelli, E., Senechal, B., Trouillet, C., Saederup, N.,
Leemput, J., Bigot, K., Campisi, L., Abitbol, M., Molina, T., Charo, I., Hume, D.A.,
Cumano, A., Lauvau, G., Geissmann, F., 2009a. CX3CR1+CD115+CD135+ common
macrophage/DC precursors and the role of CX3CR1 in their response to inam-
mation. J. Exp. Med. 206, 595606, http://dx.doi.org/10.1084/jem.20081385.
Auffray, C., Sieweke, M.H., Geissmann, F., 2009b. Blood monocytes: development,
heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27,
669692, http://dx.doi.org/10.1146/annurev.immunol.021908.132557.
Autenrieth, I.B., Tingle, A., Reske-Kunz, A., Heesemann, J., 1992. T lymphocytes medi-
ate protection against Yersinia enterocolitica in mice: characterization of murine
T-cell clones specic for Y. enterocolitica. Infect. Immun. 60, 11401149.
Autenrieth, S.E., Linzer, T.-R., Hiller, C., Keller, B., Warnke, P., Kberle, M., Bohn,
E., Biedermann, T., Bhring, H.-J., Hmmerling, G.J., Rammensee, H.-G., Aut-
enrieth, I.B., 2010. Immune evasion by Yersinia enterocolitica: differential
targeting of dendritic cell subpopulations in vivo. PLoS Pathog. 6, e1001212,
http://dx.doi.org/10.1371/journal.ppat.1001212.g008.
Autenrieth, S.E., Warnke, P., Wabnitz, G.H., Lucero Estrada, C., Pasquevich,
K.A., Drechsler, D., Gnter, M., Hochweller, K., Novakovic, A., Beer-
Hammer, S., Samstag, Y., Hmmerling, G.J., Garbi, N., Autenrieth, I.B., 2012.
Depletion of dendritic cells enhances innate anti-bacterial host defense
through modulation of phagocyte homeostasis. PLoS Pathog. 8, e1002552,
http://dx.doi.org/10.1371/journal.ppat.1002552.
Bakri, Y., 2005. Balance of MafB and PU.1 species alternative macrophage
or dendritic cell fate. Blood 105, 27072716, http://dx.doi.org/10.1182/
blood-2004-04-1448.
Baldridge, M.T., King, K.Y., Goodell, M.A., 2011. Inammatory signals regu-
late hematopoietic stem cells. Trends Immunol. 32, 5765, http://dx.doi.org/
10.1016/j.it.2010.12.003.
Banchereau, J., Steinman, R.M., 1998. Dendritic cells and the control of immunity.
Nature 392, 245252, http://dx.doi.org/10.1038/32588.
Beckerman, K.P., Rogers, H.W., Corbett, J.A., Schreiber, R.D., McDaniel, M.L., Unanue,
E.R., 1993. Release of nitric oxide during the T cell-independent pathway
of macrophage activation. Its role in resistance to Listeria monocytogenes. J.
Immunol. 150, 888895.
Belyaev, N.N., Bir, J., Langhorne, J., Potocnik, A.J., 2013. Extramedullary
myelopoiesis in malaria depends on mobilization of myeloid-restricted
progenitors by IFN- induced chemokines. PLoS Pathog. 9, e1003406,
http://dx.doi.org/10.1371/journal.ppat.1003406.s009.
Belz, G.T., Nutt, S.L., 2012. Transcriptional programming of the dendritic cell net-
work. Nat. Rev. Immunol. 12, 101113, http://dx.doi.org/10.1038/nri3149.
Belz, G.T., Zhang, L., Lay, M.D.H., Kupresanin, F., Davenport, M.P., 2007. Killer
T cells regulate antigen presentation for early expansion of memory, but
not naive, CD8+T cell. Proc. Natl. Acad. Sci. U. S. A. 104, 63416346,
http://dx.doi.org/10.1073/pnas.0609990104.
Birnberg, T., Bar-On, L., Sapoznikov, A., Caton, M.L., Cervantes-Barragn, L.,
Makia, D., Krauthgamer, R., Brenner, O., Ludewig, B., Brockschnieder, D.,
Riethmacher, D., Reizis, B., Jung, S., 2008. Lack of conventional dendritic
223
cells is compatible with normal development and T cell homeosta-
sis, but causes myeloid proliferative syndrome. Immunity 29, 986997,
http://dx.doi.org/10.1016/j.immuni.2008.10.012.
Boettcher, S., Ziegler, P., Schmid, M.A., Takizawa, H., van Rooijen, N., Kopf, M.,
Heikenwalder, M., Manz, M.G., 2012. Cutting edge: LPS-induced emergency
myelopoiesis depends on TLR4-expressing nonhematopoietic cells. J. Immunol.
188, 58245828, http://dx.doi.org/10.4049/jimmunol.1103253.
Bosschaerts, T., Guilliams, M., Stijlemans, B., Morias, Y., Engel, D., Tacke, F.,
Hrin, M., De Baetselier, P., Beschin, A., 2010. Tip-DC development dur-
ing parasitic infection is regulated by IL-10 and requires CCL2/CCR2,
IFN- and MyD88 signaling. PLoS Pathog. 6, e1001045, http://dx.doi.org/
10.1371/journal.ppat.1001045.t001.
Brocker, T., Riedinger, M., Karjalainen, K., 1997. Targeted expression of major his-
tocompatibility complex (MHC) class II molecules demonstrates that dendritic
cells can induce negative but not positive selection of thymocytes in vivo. J. Exp.
Med. 185, 541550.
Cambi, A., Gijzen, K., de Vries, I.J.M., Torensma, R., Joosten, B., Adema, G.J., Netea,
M.G., Kullberg, B.-J., Romani, L., Figdor, C.G., 2003. The C-type lectin DC-SIGN
(CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells.
Eur. J. Immunol. 33, 532538, http://dx.doi.org/10.1002/immu.200310029.
Carotta, S., Dakic, A., Amico, A.D., Pang, S.H.M., Greig, K.T., Nutt, S.L., Wu, L., 2010. The
transcription factor PU.1 controls dendritic cell development and Flt3 cytokine
receptor expression in a dose-dependent manner. Immunity 32, 628641,
http://dx.doi.org/10.1016/j.immuni.2010.05.005.
Cecchini, M.G., Dominguez, M.G., Mocci, S., Wetterwald, A., Felix, R., Fleisch, H.,
Chisholm, O., Hofstetter, W., Pollard, J.W., Stanley, E.R., 1994. Role of colony
stimulating factor-1 in the establishment and regulation of tissue macrophages
during postnatal development of the mouse. Development 120, 13571372.
Ciavarra, R.P., Taylor, L., Greene, A.R., Youseeh, N., Horeth, D., van Rooijen,
N., Steel, C., Gregory, B., Birkenbach, M., Sekellick, M., 2005. Impact of
macrophage and dendritic cell subset elimination on antiviral immunity,
viral clearance and production of type 1 interferon. Virology 342, 177189,
http://dx.doi.org/10.1016/j.virol.2005.07.031.
Copin, R., De Baetselier, P., Carlier, Y., Letesson, J.-J., Muraille, E., 2007. MyD88-
dependent activation of B220-CD11b + LY-6C+ dendritic cells during Brucella
melitensis infection. J. Immunol. 178, 51825191.
Copin, R., Vitry, M.-A., Hanot Mambres, D., Machelart, A., De Trez, C., Vanderwinden,
J.-M., Magez, S., Akira, S., Ryffel, B., Carlier, Y., Letesson, J.-J., Muraille, E., 2012.
In situ microscopy analysis reveals local innate immune response developed
around brucella infected cells in resistant and susceptible mice. PLoS Pathog. 8,
e1002575, http://dx.doi.org/10.1371/journal.ppat.1002575.g009.
Courret, N., 2006. CD11c- and CD11b-expressing mouse leukocytes transport
single Toxoplasma gondii tachyzoites to the brain. Blood 107, 309316,
http://dx.doi.org/10.1182/blood-2005-02-0666.
Dai, X.-M., Ryan, G.R., Hapel, A.J., Dominguez, M.G., Russell, R.G., Kapp, S., Sylvestre,
V., Stanley, E.R., 2002. Targeted disruption of the mouse colony-stimulating fac-
tor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deciency,
increased primitive progenitor cell frequencies, and reproductive defects. Blood
99, 111120.
Davey, G.M., Wojtasiak, M., Proietto, A.I., Carbone, F.R., Heath, W.R., Bedoui, S.,
2010. Cutting edge: priming of CD8 T cell immunity to herpes simplex virus
type 1 requires cognate TLR3 expression in vivo. J. Immunol. 184, 22432246,
http://dx.doi.org/10.4049/jimmunol.0903013.
de Bruin, A.M., Libregts, S.F., Valkhof, M., Boon, L., Touw, I.P., Nolte, M.A., 2012. IFN
induces monopoiesis and inhibits neutrophil development during inamma-
tion. Blood 119, 15431554, http://dx.doi.org/10.1182/blood-2011-07-367706.
De Smedt, T., Pajak, B., Muraille, E., Lespagnard, L., Heinen, E., De Baetselier, P., Urbain,
J., Leo, O., Moser, M., 1996. Regulation of dendritic cell numbers and maturation
by lipopolysaccharide in vivo. J. Exp. Med. 184, 14131424.
De Trez, C., Magez, S., Akira, S., Ryffel, B., Carlier, Y., Muraille, E., 2009. iNOS-producing
inammatory dendritic cells constitute the major infected cell type during the
chronic Leishmania major infection phase of C57BL/6 resistant mice. PLoS Pathog.
5, e1000494, http://dx.doi.org/10.1371/journal.ppat.1000494.s007.
De Trez, C., Pajak, B., Brait, M., Glaichenhaus, N., Urbain, J., Moser, M., Lauvau,
G., Muraille, E., 2005. TLR4 and Toll-IL-1 receptor domain-containing adapter-
inducing IFN-beta, but not MyD88, regulate Escherichia coli-induced dendritic
cell maturation and apoptosis in vivo. J. Immunol. 175, 839846.
Dinauer, M.C., Deck, M.B., Unanue, E.R., 1997. Mice lacking reduced nicotinamide
adenine dinucleotide phosphate oxidase activity show increased susceptibility
to early infection with Listeria monocytogenes. J. Immunol. 158, 55815583.
Drevets, D.A., 1999. Dissemination of Listeria monocytogenes by infected phagocytes.
Infect. Immun. 67, 35123517.
Drevets, D.A., Dillon, M.J., Schawang, J.E., Stoner, J.A., Leenen, P.J.M., 2010a. IFN-
gamma triggers CCR2-independent monocyte entry into the brain during
systemic infection by virulent Listeria monocytogenes. Brain Behav. Immun. 24,
919929, http://dx.doi.org/10.1016/j.bbi.2010.02.011.
Drevets, D.A., Dillon, M.J., Schawang, J.S., van Rooijen, N., Ehrchen, J., Sunderktter, C.,
Leenen, P.J.M., 2004. The Ly-6Chigh monocyte subpopulation transports Listeria
monocytogenes into the brain during systemic infection of mice. J. Immunol. 172,
44184424.
Drevets, D.A., Schawang, J.E., Dillon, M.J., Lerner, M.R., Bronze, M.S., Brackett,
D.J., 2008. Innate responses to systemic infection by intracellular bacteria
trigger recruitment of Ly-6Chigh monocytes to the brain. J. Immunol. 181,
529536.
Drevets, D.A., Schawang, J.E., Mandava, V.K., Dillon, M.J., Leenen, P.J.M., 2010b.
Severe Listeria monocytogenes infection induces development of monocytes
224 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
with distinct phenotypic and functional features. J. Immunol. 185, 24322441,
http://dx.doi.org/10.4049/jimmunol.1000486.
Dubois, B., Massacrier, C., Vanbervliet, B., Fayette, J., Briere, F., Banchereau, J., Caux,
C., 1998. Critical role of IL-12 in dendritic cell-induced differentiation of naive B
lymphocytes. J. Immunol. 161, 22232231.
Dubois, B., Vanbervliet, B., Fayette, J., Massacrier, C., Van Kooten, C., Briere, F.,
Banchereau, J., Caux, C., 1997. Dendritic cells enhance growth and differentiation
of CD40-activated B lymphocytes. J. Immunol. 185, 941951.
Dudziak, D., Kamphorst, A.O., Heidkamp, G.F., Buchholz, V.R., Trumpfheller, C.,
Yamazaki, S., Cheong, C., Liu, K., Lee, H.W., Park, C.G., Steinman, R.M., Nussen-
zweig, M.C., 2007. Differential antigen processing by dendritic cell subsets in
vivo. Science 315, 107111, http://dx.doi.org/10.1126/science.1136080.
Edwards, A.D., Chaussabel, D., Tomlinson, S., Schulz, O., Sher, A., Reis e Sousa, C., 2003.
Relationships among murine CD11c(high) dendritic cell subsets as revealed by
baseline gene expression patterns. J. Immunol. 171, 4760.
Efron, P.A., Martins, A., Minnich, D., Tinsley, K., Ungaro, R., Bahjat, F.R., Hotchkiss, R.,
Clare-Salzler, M., Moldawer, L.L., 2004. Characterization of the systemic loss of
dendritic cells in murine lymph nodes during polymicrobial sepsis. J. Immunol.
173, 30353043.
Endres, R., Luz, A., Schulze, H., Neubauer, H., Ftterer, A., Holland, S.M., Wagner,
H., Pfeffer, K., 1997. Listeriosis in p47(phox/ ) and TRp55/ mice: protection
despite absence of ROI and susceptibility despite presence of RNI. Immunity 7,
419432.
Flohe, S.B., 2005. Dendritic cells during polymicrobial sepsis rapidly mature but fail
to initiate a protective Th1-type immune response. J. Leukoc. Biol. 79, 473481,
http://dx.doi.org/10.1189/jlb.0705413.
Fogg, D.K., 2006. A clonogenic bone marrow progenitor specic for macrophages
and dendritic cells. Science 311, 8387, http://dx.doi.org/10.1126/science.
1117729.
Geissmann, F., Jung, S., Littman, D.R., 2003. Blood monocytes consist of two principal
subsets with distinct migratory properties. Immunity 19, 7182.
Ginhoux, F., Liu, K., Helft, J., Bogunovic, M., Greter, M., Hashimoto, D., Price, J., Yin,
N., Bromberg, J., Lira, S.A., Stanley, E.R., Nussenzweig, M., Merad, M., 2009. The
origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206,
31153130, http://dx.doi.org/10.1084/jem.20091756.
Goldszmid, R.S., Caspar, P., Rivollier, A., White, S., Dzutsev, A., Hieny, S.,
Kelsall, B., Trinchieri, G., Sher, A., 2012. NK cell-derived interferon-g orches-
trates cellular dynamics and the differentiation of monocytes into dendritic
cells at the site of infection. Immunity 36, 10471059, http://dx.doi.org/
10.1016/j.immuni.2012.03.026.
Goodyear, A., Jones, A., Troyer, R., Bielefeldt-Ohmann, H., Dow, S., 2010. Critical pro-
tective role for MCP-1 in pneumonic Burkholderia mallei infection. J. Immunol.
184, 14451454, http://dx.doi.org/10.4049/jimmunol.0900411.
Gordon, S., Taylor, P.R., 2005. Monocyte and macrophage heterogeneity. Nat. Rev.
Immunol. 5, 953964, http://dx.doi.org/10.1038/nri1733.
Greter, M., Helft, J., Chow, A., Hashimoto, D., Mortha, A., Agudo-Cantero, J., Bogunovic,
M., Gautier, E.L., Miller, J., Leboeuf, M., Lu, G., Aloman, C., Brown, B.D., Pollard,
J.W., Xiong, H., Randolph, G.J., Chipuk, J.E., Frenette, P.S., Merad, M., 2012. GM-
CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable
for the differentiation of inammatory dendritic cells. Immunity 36, 10311046,
http://dx.doi.org/10.1016/j.immuni.2012.03.027.
Grivennikov, S.I., Tumanov, A.V., Liepinsh, D.J., Kruglov, A.A., Marakusha, B.I.,
Shakhov, A.N., Murakami, T., Drutskaya, L.N., Frster, I., Clausen, B.E., Tessarollo,
L., Ryffel, B., Kuprash, D.V., Nedospasov, S.A., 2005. Distinct and nonredundant
in vivo functions of TNF produced by T cells and macrophages/neutrophils.
Immunity 22, 93104, http://dx.doi.org/10.1016/j.immuni.2004.11.016.
Guilliams, M., Ginhoux, F., Jakubzick, C., Naik, S.H., Onai, N., Schraml, B.U., Segura,
E., Tussiwand, R., Yona, S., 2014. Perspectives. Nat. Rev. Immunol. 14, 571578,
http://dx.doi.org/10.1038/nri3712.
Guilliams, M., Movahedi, K., Bosschaerts, T., VandenDriessche, T., Chuah, M.K.,
Hrin, M., Acosta-Sanchez, A., Ma, L., Moser, M., Van Ginderachter, J.A., Brys,
L., De Baetselier, P., Beschin, A., 2009. IL-10 dampens TNF/inducible nitric
oxide synthase-producing dendritic cell-mediated pathogenicity during para-
sitic infection. J. Immunol. 182, 11071118.
Heath, W.R., Carbone, F.R., 2009. Dendritic cell subsets in primary and sec-
ondary T cell responses at body surfaces. Nat. Immunol. 10, 12371244,
http://dx.doi.org/10.1038/ni.1822.
Helft, J., Ginhoux, F., Bogunovic, M., Merad, M., 2010. Origin and functional het-
erogeneity of non-lymphoid tissue dendritic cells in mice. Immunol. Rev. 234,
5575, http://dx.doi.org/10.1111/j.0105-2896.2009.00885.x.
Henderson, R.B., Hobbs, J.A.R., Mathies, M., Hogg, N., 2003. Rapid recruitment of
inammatory monocytes is independent of neutrophil migration. Blood 102,
328335, http://dx.doi.org/10.1182/blood-2002-10-3228.
Hochweller, K., Striegler, J., Hmmerling, G.J., Garbi, N., 2008. A novel CD11c.DTR
transgenic mouse for depletion of dendritic cells reveals their requirement for
homeostatic proliferation of natural killer cells. Eur. J. Immunol. 38, 27762783,
http://dx.doi.org/10.1002/eji.200838659.
Hotchkiss, R.S., Tinsley, K.W., Swanson, P.E., Grayson, M.H., Osborne, D.F., Wagner,
T.H., Cobb, J.P., Coopersmith, C., Karl, I.E., 2002. Depletion of dendritic cells, but
not macrophages, in patients with sepsis. J. Immunol. 168, 24932500.
Hsieh, C.-S., Lee, H.-M., Lio, C.-W.J., 2012. Selection of regulatory T cells in the thymus.
Nat. Rev. Immunol. 12, 157167, http://dx.doi.org/10.1038/nri3155.
Idoyaga, J., Suda, N., Suda, K., Park, C.G., Steinman, R.M., 2009. Antibody to lan-
gerin/CD207 localizes large numbers of CD8+ dendritic cells to the marginal zone
of mouse spleen. Proc. Natl. Acad. Sci. U. S. A. 106, 15241529, http://dx.doi.org/
10.1073/pnas.0812247106.
Indramohan, M., Sieve, A.N., Break, T.J., Berg, R.E., 2012. Inammatory monocyte
recruitment is regulated by interleukin-23 during systemic bacterial infection.
Infect. Immun. 80, 40994105, http://dx.doi.org/10.1128/IAI.00589-12.
Ishikawa, H., Barber, G.N., 2008. STING is an endoplasmic reticulum adap-
tor that facilitates innate immune signalling. Nature 455, 674678,
http://dx.doi.org/10.1038/nature07317.
Ishikawa, H., Ma, Z., Barber, G.N., 2009. STING regulates intracellular DNA-
mediated, type I interferon-dependent innate immunity. Nature 461, 788792,
http://dx.doi.org/10.1038/nature08476.
Izon, D., Rudd, K., DeMuth, W., Pear, W.S., Clendenin, C., Lindsley, R.C., Allman, D.,
2001. A common pathway for dendritic cell and early B cell development. J.
Immunol. 167, 13871392.
Jia, T., Leiner, I., Dorothee, G., Brandl, K., Pamer, E.G., 2009. MyD88 and type
I interferon receptor-mediated chemokine induction and monocyte recruit-
ment during Listeria monocytogenes infection. J. Immunol. 183, 12711278,
http://dx.doi.org/10.4049/jimmunol.0900460.
Jiao, X., Lo-Man, R., Guermonprez, P., Fiette, L., Deriaud, E., Burgaud, S., Gicquel, B.,
Winter, N., Leclerc, C., 2002. Dendritic cells are host cells for mycobacteria in vivo
that trigger innate and acquired immunity. J. Immunol. 168, 12941301.
Jin, L., Getahun, A., Knowles, H.M., Mogan, J., Akerlund, L.J., Packard, T.A., Per-
raud, A.-L., Cambier, J.C., 2013. STING/MPYS mediates host defense against
Listeria monocytogenes infection by regulating Ly6C(hi) monocyte migration. J.
Immunol. 190, 28352843, http://dx.doi.org/10.4049/jimmunol.1201788.
Join-Lambert, O.F., Ezine, S., Le Monnier, A., Jaubert, F., Okabe, M., Berche, P., Kayal,
S., 2004. Listeria monocytogenes-infected bone marrow myeloid cells promote
bacterial invasion of the central nervous system. Cell. Microbiol. 7, 167180,
http://dx.doi.org/10.1111/j.1462-5822.2004.00444.x.
Jung, S., Unutmaz, D., Wong, P., Sano, G.-I., De los Santos, K., Sparwasser, T., Wu,
S., Vuthoori, S., Ko, K., Zavala, F., Pamer, E.G., Littman, D.R., Lang, R.A., 2002.
In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by
exogenous cell-associated antigens. Immunity 17, 211220.
Kang, S.-J., Liang, H.-E., Reizis, B., Locksley, R.M., 2008. Regulation of hierarchical
clustering and activation of innate immune cells by dendritic cells. Immunity
29, 819833, http://dx.doi.org/10.1016/j.immuni.2008.09.017.
Kassim, S.H., Rajasagi, N.K., Ritz, B.W., Pruett, S.B., Gardner, E.M., Chervenak, R., Jen-
nings, S.R., 2009. Dendritic cells are required for optimal activation of natural
killer functions following primary infection with herpes simplex virus type 1. J.
Virol. 83, 31753186, http://dx.doi.org/10.1128/JVI.01907-08.
Klein, L., Hinterberger, M., Wirnsberger, G., Kyewski, B., 2009. Antigen presentation
in the thymus for positive selection and central tolerance induction. Nat. Rev.
Immunol. 9, 833844, http://dx.doi.org/10.1038/nri2669.
Kondo, M., Weissman, I.L., Akashi, K., 1997. Identication of clonogenic common
lymphoid progenitors in mouse bone marrow. Cell 91, 661672.
Krutzik, S.R., Tan, B., Li, H., Ochoa, M.T., Liu, P.T., Sharfstein, S.E., Graeber, T.G., Sieling,
P.A., Liu, Y.-J., Rea, T.H., Bloom, B.R., Modlin, R.L., 2005. TLR activation triggers
the rapid differentiation of monocytes into macrophages and dendritic cells.
Nat. Med. 11, 653660, http://dx.doi.org/10.1038/nm1246.
Kurihara, T., Warr, G., Loy, J., Bravo, R., 1997. Defects in macrophage recruitment
and host defense in mice lacking the CCR2 chemokine receptor. J Exp Med 186,
17571762.
Kushwah, R., Hu, J., 2011. Role of dendritic cells in the induction of regulatory T cells.
Cell Biosci. 1, 20, http://dx.doi.org/10.1186/2045-3701-1-20.
Le Borgne, M., Etchart, N., Goubier, A., Lira, S.A., Sirard, J.C., van Rooijen,
N., Caux, C., At-Yahia, S., Vicari, A., Kaiserlian, D., Dubois, B., 2006. Den-
dritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are
responsible for CD8+ T cell crosspriming in vivo. Immunity 24, 191201,
http://dx.doi.org/10.1016/j.immuni.2006.01.005.
Len, B., Lpez-Bravo, M., Ardavn, C., 2007. Monocyte-derived dendritic cells
formed at the infection site control the induction of protective T helper
1 responses against Leishmania. Immunity 26, 519531, http://dx.doi.org/
10.1016/j.immuni.2007.01.017.
Liu, C.H., Fan, Y., Dias, A., Esper, L., Corn, R.A., 2006. Cutting edge: dendritic cells
are essential for in vivo IL-12 production and development of resistance against
Toxoplasma gondii infection in mice. J. Immunol. 177, 3135.
Liu, K., Iyoda, T., Saternus, M., Kimura, Y., Inaba, K., Steinman, R.M., 2002. Immune
tolerance after delivery of dying cells to dendritic cells in situ. J. Exp. Med. 196,
10911097.
Liu, K., Nussenzweig, M.C., 2010. Development and homeostasis of dendritic cells.
Eur. J. Immunol. 40, 20992102, http://dx.doi.org/10.1002/eji.201040501.
Liu, K., Victora, G.D., Schwickert, T.A., Guermonprez, P., Meredith, M.M.,
Yao, K., Chu, F.F., Randolph, G.J., Rudensky, A.Y., Nussenzweig, M., 2009.
In vivo analysis of dendritic cell development and homeostasis. Science,
http://dx.doi.org/10.1126/science.1170540.
Loof, T.G., Rohde, M., Chhatwal, G.S., Jung, S., Medina, E., 2007. The contribution of
dendritic cells to host defenses against Streptococcus pyogenes. J. Infect. Dis. 196,
17941803, http://dx.doi.org/10.1086/523647.
Lucas, M., Schachterle, W., Oberle, K., Aichele, P., Diefenbach, A., 2007. Dendritic
cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26,
503517, http://dx.doi.org/10.1016/j.immuni.2007.03.006.
Mackarehtschian, K., Hardin, J.D., Moore, K.A., Boast, S., Goff, S.P., Lemischka, I.R.,
1995. Targeted disruption of the k2/t3 gene leads to deciencies in primitive
hematopoietic progenitors. Immunity 3, 147161.
MacNamara, K.C., Oduro, K., Martin, O., Jones, D.D., McLaughlin, M., Choi, K.,
Borjesson, D.L., Winslow, G.M., 2011. Infection-induced myelopoiesis during
intracellular bacterial infection is critically dependent upon IFN-signaling. J.
Immunol. 186, 10321043, http://dx.doi.org/10.4049/jimmunol.1001893.
 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
Majer, O., Bourgeois, C., Zwolanek, F., Lassnig, C., Kerjaschki, D., Mack, M., Mller, M.,
Kuchler, K., 2012. Type I interferons promote fatal immunopathology by regu-
lating inammatory monocytes and neutrophils during Candida infections. PLoS
Pathog. 8, e1002811, http://dx.doi.org/10.1371/journal.ppat.1002811.s005.
Manz, M.G., Traver, D., Miyamoto, T., Weissman, I.L., Akashi, K., 2001. Den-
dritic cell potentials of early lymphoid and myeloid progenitors. Blood 97,
33333341.
Marriott, I., Hammond, T.G., Thomas, E.K., et al., 1999. Salmonella efciently enter and
survive within cultured CD11c+ dendritic cells initiating cytokine expression.
Eur. J. Immunol. 29, 11071125.
Mellman, I., Steinman, R.M., 2001. Dendritic cells: specialized and regulated antigen
processing machines. Cell 106, 255258.
Merad, M., Ginhoux, F., Collin, M., 2008. Origin, homeostasis and function of Langer-
hans cells and other Langerin-expressing dendritic cells. Nat. Rev. Immunol. 8,
935947, http://dx.doi.org/10.1038/nri2455.
Merad, M., Sathe, P., Helft, J., Miller, J., Mortha, A., 2013. The dendritic cell
lineage: ontogeny and function of dendritic cells and their subsets in the
steady state and the inamed setting. Annu. Rev. Immunol. 31, 563604,
http://dx.doi.org/10.1146/annurev-immunol-020711-074950.
Miller, J.C., Brown, B.D., Shay, T., Gautier, E.L., Jojic, V., Cohain, A., Pandey, G., Leboeuf,
M., Elpek, K.G., Helft, J., Hashimoto, D., Chow, A., Price, J., Greter, M., Bogunovic,
M., Bellemare-Pelletier, A., Frenette, P.S., Randolph, G.J., Turley, S.J., Merad, M.,
2012. Deciphering the transcriptional network of the dendritic cell lineage. Nat.
Immunol. 13, 114, http://dx.doi.org/10.1038/ni.2370.
Muraille, E., Giannino, R., Guirnalda, P., Leiner, I., Jung, S., Pamer, E.G.,
Lauvau, G., 2005. Distinct in vivo dendritic cell activation by live
versus killed Listeria monocytogenes. Eur. J. Immunol. 35, 14631471,
http://dx.doi.org/10.1002/eji.200526024.
Murray, P.J., Young, R.A., Daley, G.Q., 1998. Hematopoietic remodeling in interferon-
decient mice infected with mycobacteria. Blood 91, 112.
Nagai, Y., Garrett, K.P., Ohta, S., Bahrun, U., Kouro, T., Akira, S., Takatsu, K.,
Kincade, P.W., 2006. Toll-like receptors on hematopoietic progenitor cells
stimulate innate immune system replenishment. Immunity 24, 801812,
http://dx.doi.org/10.1016/j.immuni.2006.04.008.
Naik, S.H., Metcalf, D., van Nieuwenhuijze, A., Wicks, I., Wu, L., OKeeffe, M., Short-
man, K., 2006. Intrasplenic steady-state dendritic cell precursors that are distinct
from monocytes. Nat. Immunol. 7, 663671, http://dx.doi.org/10.1038/ni1340.
Naik, S.H., Sathe, P., Park, H.-Y., Metcalf, D., Proietto, A.I., Dakic, A., Carotta, S.,
OKeeffe, M., Bahlo, M., Papenfuss, A., Kwak, J.-Y., Wu, L., Shortman, K., 2007.
Development of plasmacytoid and conventional dendritic cell subtypes from
single precursor cells derived in vitro and in vivo. Nat. Immunol. 8, 12171226,
http://dx.doi.org/10.1038/ni1522.
Narni-Mancinelli, E., Campisi, L., Bassand, D., Cazareth, J., Gounon, P., Glaichen-
haus, N., Lauvau, G., 2007. Memory CD8+ T cells mediate antibacterial immunity
via CCL3 activation of TNF/ROI+ phagocytes. J. Exp. Med. 204, 20752087,
http://dx.doi.org/10.1084/jem.20070204.
Neuenhahn, M., Kerksiek, K.M., Nauerth, M., Suhre, M.H., Schiemann, M., Gebhardt,
F.E., Stemberger, C., Panthel, K., Schrder, S., Chakraborty, T., Jung, S., Hochrein,
H., Rssmann, H., Brocker, T., Busch, D.H., 2006. CD8+ dendritic cells are
required for efcient entry of Listeria monocytogenes into the Spleen. Immunity
25, 619630, http://dx.doi.org/10.1016/j.immuni.2006.07.017.
North, R.J., 1970. The relative importance of blood monocytes and xed macrophages
to the expression of cell-mediated immunity to infection. J. Exp. Med. 132,
521534.
Obayashi, K., Doi, T., Koyasu, S., 2006. Dendritic cells suppress IgE production in B
cells. Int. Immunol. 19, 217226, http://dx.doi.org/10.1093/intimm/dxl138.
Ocuin, L.M., Bamboat, Z.M., et al., 2011. Neutrophil IL-10 suppresses periton-
eal inammatory monocytes during polymicrobial sepsis. J. Immunol. 83,
423432.
Olekhnovitch, R., Ryffel, B., Mller, A.J., Bousso, P., 2014. Collective nitric oxide
production provides tissue-wide immunity during Leishmania infection. J. Clin.
Invest. 124, 17111722, http://dx.doi.org/10.1172/JCI72058DS1.
Onai, N., Obata-Onai, A., Schmid, M.A., Manz, M.G., 2007a. Flt3 in regulation of type
I interferon-producing cell and dendritic cell development. Ann. N.Y. Acad. Sci.
1106, 253261, http://dx.doi.org/10.1196/annals.1392.015.
Onai, N., Obata-Onai, A., Schmid, M.A., Ohteki, T., Jarrossay, D., Manz, M.G., 2007b.
Identication of clonogenic common Flt3 + M-CSFR+ plasmacytoid and con-
ventional dendritic cell progenitors in mouse bone marrow. Nat. Immunol. 8,
12071216, http://dx.doi.org/10.1038/ni1518.
Palframan, R.T., Jung, S., Cheng, G., Weninger, W., Luo, Y., Dorf, M., Littman, D.R.,
Rollins, B.J., Zweerink, H., Rot, A., Von Andrian, U.H., 2001. Inammatory
chemokine transport and presentation in HEV: a remote control mechanism
for monocyte recruitment to lymph nodes in inamed tissues. J Exp Med 194,
13611373.
Palucka, A.K., 1998. Dendritic cells as the terminal stage of monocyte differentiation.
J. Immunol. 160, 45874595.
Peters, W., Scott, H.M., Chambers, H.F., Flynn, J.L., Charo, I.F., Ernst, J.D., 2001.
Chemokine receptor 2 serves an early and essential role in resistance to
Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. U. S. A. 98, 79587963,
http://dx.doi.org/10.1073/pnas.131207398.
Pne, F., Courtine, E., Ouaaz, F., Zuber, B., Sauneuf, B., Sirgo, G., Rousseau, C., Toubiana,
J., Balloy, V., Chignard, M., Mira, J.P., Chiche, J.D., 2009. Toll-like receptors 2 and 4
contribute to sepsis-induced depletion of spleen dendritic cells. Infect. Immun.
77, 56515658, http://dx.doi.org/10.1128/IAI.00238-09.
Phythian-Adams, A.T., Cook, P.C., Lundie, R.J., Jones, L.H., Smith, K.A., Barr, T.A.,
Hochweller, K., Anderton, S.M., Hammerling, G.J., Maizels, R.M., MacDonald, A.S.,
225
2010. CD11c depletion severely disrupts Th2 induction and development in vivo.
J. Exp. Med. 207, 20892096, http://dx.doi.org/10.1084/jem.20100734.
Probst, H.-C., van den Broek, M., 2005. Priming of CTLs by lymphocytic choriomenin-
gitis virus depends on dendritic cells. J. Immunol. 174, 39203924.
Proietto, A.I., van Dommelen, S., Zhou, P., Rizzitelli, A., DAmico, A., Steptoe, R.J., Naik,
S.H., Lahoud, M.H., Liu, Y., Zheng, P., Shortman, K., Wu, L., 2008. Dendritic cells
in the thymus contribute to T-regulatory cell induction. Proc. Natl. Acad. Sci. U.
S. A. 105, 1986919874, http://dx.doi.org/10.1073/pnas.0810268105.
Qiu, C.H., Miyake, Y., Kaise, H., Kitamura, H., Ohara, O., Tanaka, M., 2009. Novel
Subset of CD8+ dendritic cells localized in the marginal zone is responsi-
ble for tolerance to cell-associated antigens. J. Immunol. 182, 41274136,
http://dx.doi.org/10.4049/jimmunol.0803364.
Randolph, G.J., Furie, M.B., 1996. Mononuclear phagocytes egress from an in vitro
model of the vascular wall by migrating across endothelium in the basal to
apical direction: role of intercellular adhesion molecule 1 and the CD11/CD18
integrins. J. Exp. Med. 183, 451462.
Randolph, G.J., Inaba, K., Robbiani, D.F., Steinman, R.M., Muller, W.A., 1999. Dif-
ferentiation of phagocytic monocytes into lymph node dendritic cells in vivo.
Immunity 11, 753761.
Reizis, B., Bunin, A., Ghosh, H.S., Lewis, K.L., Sisirak, V., 2011. Plasmacytoid dendritic
cells: recent progress and open questions. Annu. Rev. Immunol. 29, 163183,
http://dx.doi.org/10.1146/annurev-immunol-031210-101345.
Robben, P.M., 2005. Recruitment of Gr-1+ monocytes is essential for con-
trol of acute toxoplasmosis. J. Exp. Med. 201, 17611769, http://dx.doi.org/
10.1084/jem.20050054.
Salazar-Gonzalez, R.M., Niess, J.H., Zammit, D.J., Ravindran, R., Srinivasan, A.,
Maxwell, J.R., Stoklasek, T., Yadav, R., Williams, I.R., Gu, X., 2006. CCR6 mediated
dendritic cell activation of pathogen-specic T cells in Peyers Patches. Immunity
24, 623632, http://dx.doi.org/10.1016/j.immuni.2006.02.015.
Sallusto, F., Lanzavecchia, A., 1994. Efcient presentation of soluble antigen by
cultured human dendritic cells is maintained by granulocyte/macrophage
colony-stimulating factor plus interleukin 4 and downregulated by tumor necro-
sis factor alpha. J. Exp. Med. 179, 11091118.
Samstein, M., Schreiber, H.A., Leiner, I.M., Susac, B., Glickman, M.S., Pamer,
E.G., 2013. Essential yet limited role for CCR2+ inammatory monocytes
during Mycobacterium tuberculosis-specic T cell priming. eLife 2, e01086,
http://dx.doi.org/10.7554/eLife.01086.
Sancho, D., Joffre, O.P., Keller, A.M., Rogers, N.C., Martnez, D., Hernanz-Falcn,
P., Rosewell, I., Sousa, C.R.E., 2009. Identication of a dendritic cell recep-
tor that couples sensing of necrosis to immunity. Nature 458, 899903,
http://dx.doi.org/10.1038/nature07750.
Sathe, P., Metcalf, D., Vremec, D., Naik, S.H., Langdon, W.Y., Huntington,
N.D., Wu, L., Shortman, K., 2014. Lymphoid tissue and plasmacytoid
dendritic cells and macrophages do not share a common macrophage-
dendritic cell-restricted progenitor. Immunity 41, 104115, http://dx.doi.org/
10.1016/j.immuni.2014.05.020.
Schindler, D., Gutierrez, M.G., Beineke, A., Rauter, Y., Rohde, M., Foster, S., Gold-
mann, O., Medina, E., 2012. Dendritic cells are central coordinators of the host
immune response to Staphylococcus aureus bloodstream infection. Am. J. Pathol.
181, 13271337, http://dx.doi.org/10.1016/j.ajpath.2012.06.039.
Schleicher, U., Liese, J., Knippertz, I., Kurzmann, C., Hesse, A., Heit, A., Fischer,
J.A.A., Weiss, S., Kalinke, U., Kunz, S., Bogdan, C., 2007. NK cell acti-
vation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12,
but is independent of plasmacytoid DCs. J. Exp. Med. 204, 893906,
http://dx.doi.org/10.1084/jem.20061293.
Schmid, M.A., Kingston, D., Boddupalli, S., Manz, M.G., 2010. Instructive cytokine
signals in dendritic cell lineage commitment. Immunol. Rev. 234, 3244,
http://dx.doi.org/10.1111/j.0105-2896.2009.00877.x.
Schmid, M.A., Takizawa, H., Baumjohann, D.R., Saito, Y., Manz, M.G., 2011. Bone
marrow dendritic cell progenitors sense pathogens via Toll-like receptors
and subsequently migrate to inamed lymph nodes. Blood 118, 48294840,
http://dx.doi.org/10.1182/blood-2011-03-344960.
Scott, H.M., Flynn, J.L., 2002. Mycobacterium tuberculosis in chemokine receptor 2-
decient mice: inuence of dose on disease progression. Infect. Immun. 70,
59465954.
Segura, E., Amigorena, S., 2013. Inammatory dendritic cells in mice and humans.
Trends Immunol. 34, 16, http://dx.doi.org/10.1016/j.it.2013.06.001.
Serbina, N.V., Hohl, T.M., Cherny, M., Pamer, E.G., 2009. Selective expansion of the
monocytic lineage directed by bacterial infection. J. Immunol. 183, 19001910,
http://dx.doi.org/10.4049/jimmunol.0900612.
Serbina, N.V., Pamer, E.G., 2006. Monocyte emigration from bone marrow during
bacterial infection requires signals mediated by chemokine receptor CCR2. Nat.
Immunol. 7, 311317, http://dx.doi.org/10.1038/ni1309.
Serbina, N.V., Salazar-Mather, T.P., Biron, C.A., Kuziel, W.A., Pamer, E.G., 2003.
TNF/iNOS-producing dendritic cells mediate innate immune defense against
bacterial infection. Immunity 19, 5970.
Shi, C., Jia, T., Mendez-Ferrer, S., Hohl, T.M., Serbina, N.V., Lipuma, L.,
Leiner, I., Li, M.O., Frenette, P.S., Pamer, E.G., 2011. Bone marrow mes-
enchymal stem and progenitor cells induce monocyte emigration in
response to circulating toll-like receptor ligands. Immunity 34, 590601,
http://dx.doi.org/10.1016/j.immuni.2011.02.016.
Sponaas, A.-M., Freitas do Rosario, A.P., Voisine, C., Mastelic, B., Thompson, J.,
Koernig, S., Jarra, W., Renia, L., Mauduit, M., Potocnik, A.J., Langhorne, J.,
2009. Migrating monocytes recruited to the spleen play an important role
in control of blood stage malaria. Blood 114, 55225531, http://dx.doi.org/
10.1182/blood-2009-04-217489.
226 K. Bieber, S.E. Autenrieth / Immunobiology 220 (2015) 215226
Sponaas, A.M., 2006. Malaria infection changes the ability of splenic dendritic cell
populations to stimulate antigen-specic T cells. J. Exp. Med. 203, 14271433,
http://dx.doi.org/10.1084/jem.20052450.
Steinman, R.M., et al., 2002. Avoiding horror autotoxicus: the importance of dendritic
cells in peripheral T cell tolerance. Proc. Natl. Acad. Sci. U. S. A. 99, 351358.
Steinman, R.M., Banchereau, J., 2007. Taking dendritic cells into medicine. Nature
449, 419426, http://dx.doi.org/10.1038/nature06175.
Sunderktter, C., Nikolic, T., Dillon, M.J., van Rooijen, N., Stehling, M., Drevets, D.A.,
Leenen, P.J.M., 2004. Subpopulations of mouse blood monocytes differ in matu-
ration stage and inammatory response. J. Immunol. 172, 44104417.
Sundquist, M., Wick, M.J., 2005. TNF-alpha-dependent and -independent maturation
of dendritic cells and recruited CD11c(int) CD11b+ cells during oral Salmonella
infection. J. Immunol. 175, 32873298.
Sundquist, M., Wick, M.J., 2009. Salmonella induces death of CD8+ dendritic cells but
not CD11cint CD11b+ inammatory cells in vivo via MyD88 and TNFR1. J. Leukoc.
Biol. 85, 225234, http://dx.doi.org/10.1189/jlb.0708413.
Tam, M.A., Wick, M.J., 2004. Dendritic cells and immunity to Listeria:
TipDCs are a new recruit. Trends Immunol. 25, 335339, http://dx.doi.org/
10.1016/j.it.2004.05.004.
Tam, M.A., Wick, M.J., 2006. Differential expansion, activation and effector func-
tions of conventional and plasmacytoid dendritic cells in mouse tissues
transiently infected with Listeria monocytogenes. Cell. Microbiol. 8, 11721187,
http://dx.doi.org/10.1111/j.1462-5822.2006.00700.x.
Taylor, P.R., Brown, G.D., Geldhof, A.B., Martinez-Pomares, L., Gordon, S., 2003.
Pattern recognition receptors and differentiation antigens dene murine
myeloid cell heterogeneity ex vivo. Eur. J. Immunol. 33, 20902097,
http://dx.doi.org/10.1002/eji.200324003.
Tian, T., Woodworth, J., Skld, M., Behar, S.M., 2005. In vivo depletion of CD11c+ cells
delays the CD4+ T cell response to Mycobacterium tuberculosis and exacerbates
the outcome of infection. J. Immunol. 175, 32683272.
Tittel, A.E.P., Heuser, C., Ohliger, C., Llanto, C., Yona, S., mmerling, G.U.N.J.H.A.,
Engel, D.R., Garbi, N., Kurts, C., 2012. Functionally relevant neutrophilia
in CD11c diphtheria toxin receptor transgenic mice. Nat. Methods, 17,
http://dx.doi.org/10.1038/nmeth.1905.
Tripp, C.S., Wolf, S.F., Unanue, E.R., 1993. Interleukin 12 and tumor necrosis
factor alpha are costimulators of interferon gamma production by natural
killer cells in severe combined immunodeciency mice with listeriosis, and
interleukin 10 is a physiologic antagonist. Proc. Natl. Acad. Sci. U. S. A. 90,
37253729.
Tsou, C.-L., Peters, W., Si, Y., Slaymaker, S., Aslanian, A.M., Weisberg, S.P., Mack, M.,
Charo, I.F., 2007. Critical roles for CCR2 and MCP-3 in monocyte mobilization
from bone marrow and recruitment to inammatory sites. J. Clin. Invest. 117,
902909, http://dx.doi.org/10.1172/JCI29919.
Varol, C., Landsman, L., Fogg, D.K., Greenshtein, L., Gildor, B., Margalit, R.,
Kalchenko, V., Geissmann, F., Jung, S., 2007. Monocytes give rise to mucosal,
but not splenic, conventional dendritic cells. J. Exp. Med. 204, 171180,
http://dx.doi.org/10.1084/jem.20061011.
Verschoor, A., Neuenhahn, M., Navarini, A.A., Graef, P., Plaumann, A., Seidlmeier,
A., Nieswandt, B., Massberg, S., Zinkernagel, R.M., Hengartner, H., Busch, D.H.,
2011. A platelet-mediated system for shuttling blood-borne bacteria to CD8+
dendritic cells depends on glycoprotein GPIb and complement C3. Nat. Immunol.
12, 11941201, http://dx.doi.org/10.1038/ni.2140.
Villadangos, J.A., Schnorrer, P., 2007. Intrinsic and cooperative antigen-presenting
functions of dendritic-cell subsets in vivo. Nat. Rev. Immunol. 7, 543555,
http://dx.doi.org/10.1038/nri2103.
Vremec, D., Pooley, J., Hochrein, H., Wu, L., Shortman, K., 2000. CD4 and CD8 expres-
sion by dendritic cell subtypes in mouse thymus and spleen. J. Immunol. 164,
29782986.
Wan, S., Zhou, Z., Duan, B., Morel, L., 2008. Direct B cell stimulation by den-
dritic cells in a mouse model of lupus. Arthr. Rheum. 58, 17411750,
http://dx.doi.org/10.1002/art.23515.
Waskow, C., Liu, K., Darrasse-Jze, G., Guermonprez, P., Ginhoux, F., Merad, M., Shen-
gelia, T., Yao, K., Nussenzweig, M., 2008. The receptor tyrosine kinase Flt3 is
required for dendritic cell development in peripheral lymphoid tissues. Nat.
Immunol. 9, 676683, http://dx.doi.org/10.1038/ni.1615.
Wu, L., DAmico, A., Hochrein, H., OKeeffe, M., Shortman, K., Lucas, K., 2001.
Development of thymic and splenic dendritic cell populations from different
hemopoietic precursors. Blood 98, 33763382.
Yarovinsky, F., 2005. TLR11 activation of dendritic cells by a protozoan prolin-like
protein. Science 308, 16261629, http://dx.doi.org/10.1126/science.1109893.
Ynez, A., Megas, J., OConnor, J.-E., Gozalbo, D., Gil, M.L., 2011. Candida
albicans induces selective development of macrophages and monocyte derived
dendritic cells by a TLR2 dependent signalling. PLoS ONE 6, e24761,
http://dx.doi.org/10.1371/journal.pone.0024761.g009.
Ynez, A., Murciano, C., OConnor, J.-E., Gozalbo, D., Gil, M.L., 2009. Candida
albicans triggers proliferation and differentiation of hematopoietic stem and
progenitor cells by a MyD88-dependent signaling. Microb. Infect. 11, 531535,
http://dx.doi.org/10.1016/j.micinf.2009.01.011.