REVIEWS

Immune cell crosstalk in type 1

diabetes
Agnès Lehuen*, Julien Diana*, Paola Zaccone‡ and Anne Cooke‡
Abstract | The development of type 1 diabetes involves a complex interaction between pancreatic
β-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions
between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have
highlighted how these different cell populations can influence the onset of autoimmunity. There
is evidence that infection can have either a potentiating or inhibitory role in the development of
type 1 diabetes. Interactions between pathogens and cells of the innate immune system, and
how this can influence whether T cell activation or tolerance occurs, have been under close
scrutiny in recent years. This Review focuses on the nature of this crosstalk between the innate
and the adaptive immune responses and how pathogens influence the process.

Non-obese diabetic (NOD)

mice
Mice that spontaneously
develop type 1 diabetes as a
result of islet antigen-specific
T cell-mediated destruction of
pancreatic β-cells.
*Institut National de la Santé
et de la Recherche Médicale
(INSERM) U986, Hôpital
Saint Vincent de Paul,
Bâtiment Petit, 82 Avenue
Denfert-Rochereau,
75014 Paris, France.
‡
Department of Pathology,
University of Cambridge,
Tennis Court Rd, Cambridge
CB21QP, UK.
Correspondence to A.L.
and A.C.
e-mails:
agnes.lehuen@inserm.fr;
ac@mole.bio.cam.ac.uk
doi:10.1038/nri2787
Type 1 diabetes (T1D) is a chronic autoimmune dis-
ease, during which the pancreatic β-cells (which secrete
insulin) are selectively destroyed. It is thought to be a
T helper 1 (TH1) cell-mediated disease that involves
CD8+ T cells and innate immune cells. Individuals with
T1D develop hyperglycaemia and can develop diabetes-
associated complications in several organ systems owing
to a lack of insulin. This was a lethal disease until the
1920s when Banting and Best 1 identified insulin as
the hormone in the pancreas responsible for maintain-
ing blood glucose homeostasis. The development of T1D
is under polygenic control, with an additional role for
environmental factors2. This role for environmental fac-
tors is highlighted by the 40–60% concordance rate for
diabetes onset in identical twins and also by the dramatic
increase in the incidence of T1D in recent years3,4. As the
development of T1D is increasing in the UK at a rate of
3% per year, which is faster than can be accounted for
by genetic change, there has been a considerable effort
to identify the environmental factors that predispose an
individual to diabetes onset. There has been substantial
focus on identifying agents, such as viruses, that might
precipitate diabetes onset and, more recently, there has
been a growing interest in establishing whether exposure
to certain pathogens might have been the reason for a
historically lower incidence of diabetes onset. Improved
sanitation and living conditions, together with vaccina-
tion strategies, have decreased our exposure to pathogens
and development of infectious disease. It is therefore pos-
sible that a reduced exposure to pathogens might be the
environmental alteration over the last 60 years that has
had a role in the increased incidence of T1D5.
Studies in animal models (BOX 1) , particularly in
non-obese diabetic (NOD) mice, have identified roles for
several different immune cell types in β-cell destruc-
tion. CD4+ and CD8+ T cells, as well as macrophages,
have been shown to have a role in β-cell death. However,
other cell types are present in the pancreatic infiltrate
and in the pancreatic draining lymph node, where the
initial presentation of islet antigen by dendritic cells
(DCs) to islet antigen-specific T cells occurs6. These
cells include B cells, natural killer (NK) cells and
NKT cells, as well as DC subsets, and they could also
contribute to β-cell death. Conversely, targeting or har-
nessing the activities of many of these different immune
cell types can also be effective in inhibiting β-cell
destruction. This strongly suggests that there is substan-
tial crosstalk between the immune cells that are involved
in pathogenesis and those involved in immune regula-
tion. The genetics of T1D or therapeutic approaches
for disease prevention have been extensively reviewed
elsewhere7,8 and therefore are not discussed here.
Epidemiological studies suggest that environ-
mental factors influence the development of T1D
in humans9,10. Pathogens, particularly viruses, could
accelerate T1D onset through the induction of inflam-
matory responses following direct infection of β-cells,
as well as through other mechanisms (discussed
below). In addition, other pathogens might inhibit
T1D onset through effects on numerous cell types and
the induction of mediators that suppress host pathol-
ogy. These contrasting effects are mediated through
interactions between cells of both the innate and
adaptive immune system. In this Review, we discuss

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REVIEWS
Box 1 | Animal models of type 1 diabetes
Animal models have contributed enormously to the understanding of processes
leading to development of type 1 diabetes (T1D). T1D can be experimentally induced
in laboratory animals with chemicals (such as streptozotocin and cyclophosphamide in
genetically susceptible mouse strains) or by genetic manipulation (such as transgenic
mice). In addition, two spontaneous murine models have been extensively used to
understand the pathophysiology of T1D: the biobreeding (BB) rat and the non-obese
diabetic (NOD) mouse models. In BB rats there is no sex difference in the incidence of
T1D, but female NOD mice develop T1D at a higher incidence than male NOD mice.
Besides this difference, both models resemble T1D in humans, including the presence
of islet antigen-specific CD4+ and CD8+ T cells and genetic linkage to disease.
As in humans, specific MHC gene products are involved in T1D susceptibility in both
models: RT1u/u in BB rats and I–Ag7 in NOD mice. In addition to the MHC locus, other
loci contribute to disease development. No less than 12 loci were found to influence
the diabetogenic process in BB rats, and more than 20 potential Idd loci have been
identified in NOD mice, which include polymorphisms in the genes cytotoxic
T lymphocyte antigen 4 (Ctla4), interleukin-2 (Il2) and protein tyrosine phosphatase,
non-receptor type 22 (Ptpn22). In the past 20 years, numerous studies have shown that
both genetic and environmental factors contribute to the pathogenesis of the disease
in both models. In particular, infection studies have underlined the importance of
co-evolution between pathogens and the mammalian immune system for both the
induction and prevention of T1D.
the role of innate immune cells in promoting or pre-
venting diabetes onset and the potential for infection
to influence the crosstalk between immune cells and
pancreatic β-cells.
Lymphocytes and T1D
There is considerable evidence that T cells have an
important role in the development and progression of
T1D in both humans and animal models. The recur-
rence of T1D in recipients of segmental pancreas grafts
from HlA-identical donors showed a clear role for
T cells — particularly CD8+ T cells — and monocytes,
with little evidence for a humoral immune response,
in β-cell destruction11. β-cell survival could only be
achieved in these transplantation studies if the recipi-
ent was immunosuppressed, indicating that T1D in
humans was an autoimmune disease.
Studies in NoD mice have shown that T1D develop-
ment depends on both CD4+ and CD8+ T cells: T1D can
only be transferred to immunocompromised syngeneic
recipients by a combination of splenic CD4+ and CD8+
T cells from donor NoD mice but not by either T cell
subset alone12. The ability of a CD3-specific antibody,
which induces T cell tolerance, to reverse T1D onset in
NoD mice emphasized the key role of T cells in sus-
tained β-cell destruction13. These studies led the way
X-linked
agammaglobulinaemia
to the use of an aglycosyl CD3-specific monoclonal
A human immunodeficiency antibody in patients with recent-onset T1D, in which
that is caused by mutations in there was evidence that targeting T cells resulted in
the gene encoding Bruton’s suppression of ongoing β-cell destruction14.
tyrosine kinase (BTK) (which is
There are several ways in which T cell-mediated
located on the X chromosome).
These mutations result in a β-cell death might occur (FIG. 1). CD8+ T cells could
block in B cell maturation and kill pancreatic β-cells through mHC class I-mediated
in poor antibody production. cytotoxicity, and both CD4+ and CD8+ T cells produce
A naturally occurring mouse cytokines, such as interferon-γ (IFNγ), that induce
mutant of BTK, X-linked
immune deficiency, is
expression of the death receptor FAS (also known as
associated with less severe CD95) and chemokine production by β-cells. Activation
disease. of FAS by FAS ligand (FASl)-expressing activated T cells
502 | jUly 2010 | volUmE 10
© 2010 Macmillan Publishers Limited. All rights reserved
could initiate β-cell apoptosis. Chemokine production
by β-cells results in further recruitment of mononuclear
cells to the site, thereby enhancing inflammation15. In
addition, IFNγ can activate macrophages and induce
increased pro-inflammatory cytokine production,
including interleukin-1β (Il-1β) and tumour necrosis
factor (TNF). β-cells express high levels of Il-1 recep-
tor and seem to be more sensitive to Il-1β-induced
apoptosis than other endocrine cells in the islet. This
crosstalk between T cells and macrophages undoubtedly
exacerbates the immune-mediated stress on β-cells and
contributes to their destruction. IFNγ, Il-1β and TNF
also induce the expression of reactive oxygen species
(RoS) including nitric oxide by β-cells, and RoS have
the potential to mediate apoptosis.
Although T cells have a pathological role in T1D
onset, there is also evidence supporting a role for
T cells in the prevention of β-cell destruction. Patients
with IPEX (immunodysregulation, polyendocrinopathy,
enteropathy, X-linked) syndrome — who have muta-
tions in forkhead box P3 (FoXP3; the regulatory
T (TReg) cell-associated transcription factor) — can
develop T1D16, which highlights the importance of
TReg cells in controlling the onset of this autoimmune
disease. Studies in NoD mice have shown the impor-
tance of TReg cells in preventing T1D: CD28-deficient
NoD mice, which lack TReg cells, develop accelerated
disease17. In addition, strategies such as injection of
Il-2 to increase TReg cell numbers are seen as a potential
therapeutic approach18.
T cells are clearly pivotal for T1D development,
but there are also data suggesting an involvement of
other cell types such as B cells; however, there is little
evidence for a role for antibody in the pathogenesis of
T1D. B cell depletion in NoD mice, either through gene
targeting or antibody treatment, impairs the develop-
ment of T1D19,20. This has led to the treatment of newly
diagnosed T1D patients with the B cell-depleting
monoclonal antibody rituximab (Rituxan/mabthera;
Genentech/Roche/Biogen Idec), resulting in improved
β-cell function21. However, there is one description
of a patient with X-linked agammaglobulinaemia who
developed T1D22, which questions the role of B cells
in disease pathogenesis. It may be that B cells have a
role as antigen-presenting cells that maintain islet
antigen-specific T cell activity 19,23.
Innate immune cells in T1D
As islet antigen-specific T cells can differentiate into
either pathogenic effector T cells (diabetogenic T cells)
or protective TReg cells, many studies have investigated
the role of innate immune cells in T1D, as these cells usu-
ally determine the type of immune response that ensues.
Innate cells producing pro-inflammatory or suppres-
sive cytokines define the milieu in which islet antigen-
specific T cells are activated and whether a deleterious or
protective local immune response occurs in the pancreas
(FIG. 2). we first discuss studies pertaining to the patho-
genic role of innate immune cells, such as macrophages,
NK cells and DCs, and then review the growing evidence
for the protective effect of innate immune cells.
www.nature.com/reviews/immunol
 REVIEWS

The pathogenic role of macrophages. Although numer-

ous studies of both humans and NoD mice emphasize a
predominant role for diabetogenic T cells in the patho-
Macrophage genesis of T1D, several studies support the involvement
of macrophages in this disease24–28. Early experiments
described the presence of macrophages in islet infil-
trates of NoD mice, and showed that inhibition of the
Lymphocyte and
macrophage recruitment macrophage influx into the pancreas, by blocking an
by CXCL10, CCL2 and CCL20 adhesion-promoting receptor on this cell, inhibited
IFNγ TNF the development of T1D24. In vitro and in vivo studies
IL-12
IL-1β
in mice and rats showed that the deleterious effect of
macrophages on β-cells can be mediated through the
Apoptosis
production of TNF and Il-1β29,30. Interestingly, pro-
or induction RAE1 NKG2D inflammatory macrophages can be detected in pancre-
Microbial
products of IDO atic islets before T cell infiltration, as well as in NoD/scid
β-cell damage NK cell
(severe combined immunodeficient) mice, which lack
TLR2 Degranulation functional B and T cells30.
NKp46 macrophages have been shown to produce Il-12
β-cell Unknown (ReF. 26) and to promote efficient differentiation of
TLR4 TLR3 TLR9 ligand
diabetogenic CD8+ cytotoxic T lymphocytes (CTls)
Chromogranin A Cytotoxicity leading to T1D onset25. Genetic differences in Il-12 pro-
Insulin duction have been observed in peritoneal macrophages
Pro-insulin MHC class I from susceptible and resistant mouse strains: cells from
Tolerance β-cell NoD mice secrete more Il-12 than those from non-obese
or antigen
resistant (NOR) mice when stimulated with CD40 ligand or
apoptosis TCR
lipopolysaccharide (lPS)26. more recent data suggest that
PDL1 recruitment of macrophages to islets is mediated by the
WE14 peptide PDL1 FAS PD1 secretion of CC-chemokine ligand 1 (CCl1) and CCl2
Diabetogenic
PD1 FASL CD8+ T cell by CD4+ T cells and pancreatic β-cells, respectively 27,31.
macrophages recruited to the pancreas produce Il-1β,
TNF and RoS that can cause β-cell death, revealing an
TCR additional role for macrophages in the destructive phase
Diabetogenic
DC CD4+ T cell of T1D. Finally, TNF- and Il-1β-producing macrophages
MHC and DCs have been observed in pancreatic islet infiltrates
class II from patients with recent-onset T1D32. Together, these
studies support a pathogenic role for macrophages in
both the initiation and destruction phases of T1D.

A role for NK cells. NK cells mediate early protection

against viruses and are involved in the killing of infected
Figure 1 | molecules expressed by pancreatic β-cells involved in their destruction cells and tumours. NK cells are both cytotoxic and pro-
or protection. Toll-like receptors (TLRs) are expressed by pancreatic β-cells to detect ducers of cytokines, particularly IFNγ. Thus, NK cells
Nature Reviews | Immunology
danger from microbial products and can trigger type 1 diabetes (T1D); for example, could contribute directly and indirectly to the destruction
during a localized virus infection in the pancreas. Cytokines, such as interleukin-1β of β-cells. NK cells have been detected in the pancreas of
(IL-1β), IL-12, interferon-γ (IFNγ) and tumour necrosis factor (TNF), secreted by patients with T1D and in many T1D mouse models33–37.
immune cells, such as macrophages, dendritic cells (DCs), CD4+ and CD8+ T cells and
moreover, several reports have described a correlation
natural killer (NK) cells, could cause direct damage (such as apoptosis) of β-cells but
could also induce self-defence mechanisms; for example, IFNγ induces indoleamine between the frequency and/or activation of NK cells with
2,3-dioxygenase (IDO) expression by β-cells. Chemokines such as CXC-chemokine the destructiveness of the pancreatic infiltrate35,38.
ligand 10 (CXCL10), CC-chemokine ligand 2 (CCL2) and CCL20 secreted by β-cells NK cells isolated from the pancreas of NoD mice have
recruit macrophages and other inflammatory cells to the islet area. Natural killer a more activated phenotype than those isolated from the
group 2, member D (NKG2D) expressed by NK cells binds to retinoic acid early spleen and pancreatic lymph node, with higher expres-
transcript 1 (RAE1) expressed by β-cells in non-obese diabetic (NOD) mice, and is sion of CD25, CD69, programmed cell death 1 (PD1)
associated with β-cell damage. NKp46 engagement by an unknown ligand on β-cells and killer cell lectin-like receptor group G, member 1
causes degranulation of NK cells. Negative co-stimulatory molecules, such as (KlRG1)37. They also proliferate more and spontane-
programmed cell death ligand 1 (PDL1) expressed by β-cells can modulate ously produce higher levels of IFNγ and express CD107a
diabetogenic T cell attack. β-cell antigens (such as peptides derived from insulin
on their cell surface (a marker of granule exocytosis),
or pro-insulin) can be presented by MHC class I molecules and recognized by
diabetogenic CD8+ T cells. MHC class II molecules expressed by antigen-presenting reflecting their cytotoxic function39. Interestingly, NK
cells such as DCs can also present β-cell antigens (peptides such as WE14 from cells were observed in the pancreas in NoD mice before
chromogranin A, insulin and pro-insulin) that can induce islet antigen-specific CD4+ T cell infiltration and in the pancreas of NoD–Rag mice
T cell expansion. FASL-expressing T cells can mediate apoptosis through interaction (which lack mature B and T cells), suggesting that they
with FAS expressed on β-cells. TCR, T cell receptor. could have a sentinel role in the pancreas.

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REVIEWS

Phase I: β-cell death and Phase III: immune cell crosstalk and induction or prevention of β-cell death
APC activation
NK cell Macrophage cDC

β-cell damage: apoptosis

and viral infection

IFNγ,
granzymes, TNF, IL-1β and
and nitric oxide
IL-10 and TGFβ
perforin IL-12
β-cell
β-cell IFNγ, granzymes
antigen and perforin TReg cell
β-cell Diabetogenic
T cell
PDL1–PD1 pDC iNKT cell
cDC
Cell death
IDO
Pancreas

Draining lymph node

Promote
recruitment

iNKT cell IDO, IL-10,

TGFβ and ICOSL
Activated
cDC
PDL1–PD1
MHC
Activation
TCR Tolerogenic cDC

IL-12

Phase II: expansion of IDO, IL-10,

Macrophage Pathogenic islet
antigen-specific T cell
Non-obese resistant (NOR)
mice
NOR mice have the identical
T cell developmental
background as NOD mice, but
they do not spontaneously
develop type 1 diabetes.
BDC2.5 TCR-transgenic
NOD mice
T cells in these mice express a
TCR specific for a pancreatic
antigen but, interestingly, these
mice have a decreased
incidence of type 1 diabetes
and develop a non-invasive
insulitis. These mice are
used as donors of islet
antigen-specific CD4+ T cells
and manipulation of these
mice, such as injection of
blocking CTLA4-specific
antibody and infection with
coxsackie virus B4, induces
rapid type 1 diabetes.
pathogenic or regulatory TGFβ and
islet antigen-specific T cells TReg cell ICOSL pDC
Figure 2 | Cellular and molecular mechanisms in the development or prevention of type 1 diabetes. The
initiation phase of type 1 diabetes (T1D) takes place in the pancreas, where conventional dendritic cells (cDCs) capture
and process β-cell antigens. β-cell damage can occur by ‘natural’ apoptosis or after viral infections. Invariant
Nature Reviews natural
| Immunology
killer T (iNKT) cells and plasmacytoid DCs (pDCs) control viral replication, preventing subsequent inflammation and
T1D (not shown). Activated cDCs prime pathogenic islet antigen-specific T cells after migration to the draining lymph
node, and macrophages promote this activation through interleukin-12 (IL-12) secretion. B cells present β-cell antigen
to diabetogenic T cells and secrete autoantibodies (not shown). The activation of islet antigen-specific T cells can be
inhibited by cDCs through various mechanisms, such as engagement of programmed cell death ligand 1 (PDL1).
iNKT cells can promote the recruitment of tolerogenic cDCs and pDCs that could expand regulatory T (TReg) cells
through the production of indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ) and
inducible T cell co-stimulator ligand (ICOSL). In the pancreas, β-cells can be killed by diabetogenic T cells and NK cells
through the release of interferon-γ (IFNγ), granzymes and perforin, as well as by macrophages through the production
of tumour necrosis factor (TNF), IL-1β and nitric oxide. IL-12 produced by cDCs sustains the effector functions of
activated diabetogenic T cells and NK cells (not shown). β-cell damage can be inhibited by TReg cells that inhibit
diabetogenic T cells and innate immune cells through IL-10 and TGFβ. Tolerogenic pDCs stimulated by iNKT cells could
also control diabetogenic T cells through IDO production. Lastly, β-cells can inhibit diabetogenic T cells by expressing
PDL1. This complex crosstalk between innate and adaptive immune cells results in the development or the prevention
of T1D. APC, antigen-presenting cell; TCR, T cell receptor.
A pathogenic role for NK cells has been suggested in (cytotoxic T lymphocyte antigen 4)-specific antibody
various T1D mouse models such as NoD mice, SoCS1 treated BDC2.5 TCR-transgenic NOD mice 34–36 (BOX 1).
(suppressor of cytokine signalling 1)-transgenic NoD Depletion of NK cells using various antibodies against
mice infected with coxsackie virus B4, mice trans- NK1.1 and asialo-Gm1 (ReFs 34–36) prevented T1D in
genically expressing IFNβ in their β-cells, and CTlA4 all of these models. Natural killer group 2, member D

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© 2010 Macmillan Publishers Limited. All rights reserved


RIP–LCMV transgenic
model
A transgenic mouse model of
type 1 diabetes in which
peptides derived from
lymphocytic choriomeningitis
(LCMV) are expressed in the
pancreas under the control of
the rat insulin promoter (RIP).
Infection of the mice with
LCMV leads to the
development of type 1
diabetes as a result of
infiltrating CD8+ effector
T cells.
Perforin
A component of cytolytic
granules that participates in
the permeabilization of plasma
membranes, allowing
granzymes and other cytotoxic
components to enter target
cells.
Peripheral tolerance
The lack of self responsiveness
of mature lymphocytes in the
periphery to specific antigens.
These mechanisms control
potentially self-reactive
lymphocytes that have
escaped central tolerance.
Peripheral tolerance is
associated with the
suppression of production of
self-reactive antibodies by
B cells and inhibition of
self-reactive effector cells, such
as cytotoxic T lymphocytes.
T cell anergy
A state of T cell
unresponsiveness to
antigen-specific stimulation. It
can be induced by stimulation
with a large amount of specific
antigen in the absence of the
engagement of co-stimulatory
molecules.
NATURE REvIEwS | Immunology
(NKG2D) and NKp46 are expressed by NK cells, and
recent studies suggest that their ligands (retinoic acid
early transcript 1 (RAE1) and NKp46 ligand, respec-
tively) are expressed by β-cells from NoD mice 40.
moreover, NKG2D and NKp46 blockade could pre-
vent T1D in NoD mice, suggesting that recognition of
β-cells by NK cells may have a role in T1D39. However,
although NKp46 expression is restricted to NK cells,
NKG2D is also expressed by CTls, and NKG2D block-
ade might affect the function of diabetogenic CTls that
infiltrate the pancreas 40. The deleterious role of NK
cells in T1D has been further highlighted in a recent
study 38: TReg cell depletion of BDC2.5 TCR-transgenic
NoD mice resulted in an increase in the percent-
age of activated pancreatic NK cells that produced
large amounts of effector molecules such as IFNγ,
which promote the effector function of diabetogenic
CD4+ T cells.
How do DCs promote T1D? Early studies described
the presence of antigen-presenting cells (APCs) in
transplanted pancreatic islets41 and showed that deple-
tion of these cells facilitated graft survival in mice42.
These data suggested that APCs could take up and
process β-cell-derived proteins and subsequently ini-
tiate the diabetogenic response. This hypothesis was
tested using mice that express the lymphocytic chorio-
meningitis virus (lCmv) glycoprotein under the con-
trol of the rat insulin promoter (RIP) (the RIP–LCMV
transgenic model)43. Repeated injection of conventional
DCs (cDCs) constitutively expressing the immuno-
dominant lCmv epitope into these transgenic mice
resulted in severe destructive mononuclear infiltra-
tion of the pancreatic islets and development of T1D
through CTl activation. This development of CTl-
mediated T1D was perforin independent, as it was also
seen in perforin-deficient RIP–lCmv mice43. Further
studies showed that self antigens released after β-cell
death could be captured by cDCs in the pancreatic
islets and presented to islet antigen-specific T cells
in the pancreatic lymph node where the diabetogenic
response is initiated6,44.
Initial β-cell death could occur physiologically in
NoD mice at two weeks of age during tissue remodel-
ling and at weaning owing to a metabolic change, or
it could occur through injury mediated by viral infec-
tions6,10. Such β-cell death could activate cDCs and
initiate priming of islet antigen-specific CD4+ T cells,
as revealed by the high frequency of cDCs present-
ing β-cell-derived antigens in the pancreatic draining
lymph node6. A role for Toll-like receptor 2 (TlR2) in
this process has been suggested45, but a recent study
showed similar T1D incidence in TlR2-deficient and
wild-type NoD mice46. However, it is conceivable that
other pattern recognition receptors (PRRs) may have a
role in the absence of TlR2. Several reports have sug-
gested that cDCs from NoD mice have increased abil-
ity to activate T cells through higher Il-12 production
and co-stimulatory molecule expression47,48. Together,
these studies support a diabetogenic role for cDCs in the
initiation of this disease.
© 2010 Macmillan Publishers Limited. All rights reserved
REVIEWS
Plasmacytoid DCs (pDCs) detect viral RNA or DNA
through TlR7 and TlR9 and respond by secreting
large amounts of type I IFNs, Il-12 and pro-inflam-
matory chemokines. In contrast to cDCs, pDCs have a
decreased capacity to take up, process and present solu-
ble antigens49. A putative role for pDCs in the devel-
opment of T1D is supported by observations in both
human and murine models that type I IFNs, which are
usually produced by this cell type, can in some situa-
tions induce or enhance T1D50,51. Antibody-mediated
blockade of type I IFNs identified a crucial role for these
cytokines in the initiation of disease. However, these
studies did not show that pDCs were the source of this
type I IFN. mouse models have been used to examine
the pDC populations in the pancreas and pancreatic
lymph node at the early stage of T1D development.
Two reports suggest a pathogenic role for pDCs in NoD
mice. In one study, the initiation of T1D correlated with
an increased production of type I IFNs by pDCs in the
pancreatic lymph node52. FmS-like tyrosine kinase 3
ligand (FlT3l) treatment, which expands both cDC
and pDC populations, accelerated T1D in 15-week-old
NoD mice, an age when islet antigen-specific CTls
were detectable in blood53.
However, there have been apparently discrepant data
regarding the frequency of pDCs in the blood of patients
with T1D, which may reflect differences in the time
when the blood samples were taken54–56. Interestingly,
pDCs from early-diagnosed patients were shown to
present immune complexes to T cells more efficiently
than cDCs, suggesting a possible detrimental role of
pDCs in T1D onset.
Prevention of T1D by DCs. It is known that patients
with a congenital DC deficiency develop autoimmune
diseases57. This highlights a role for DCs in mediating
peripheral tolerance and, indeed, antigen presentation by
cDCs mediates tolerance by inducing T cell deletion, T cell
anergy or the expansion of antigen-specific TReg cells58. TReg
cells are key players in preventing T1D18, and various stud-
ies have investigated whether modulation of cDCs could
influence TReg cells and T1D development. Treatment of
NoD mice with granulocyte colony-stimulating factor
(G-CSF) to mobilize DCs prevented T1D development
and increased the numbers of cDCs and pDCs in the
spleen59. These cells mediated tolerance through effects
on CD4+CD25+ TReg cells that suppress pathogenic T cells
through the production of transforming growth factor-β
(TGFβ)59. FlT3l injection protected NoD mice from
T1D by enhancing CD4+CD25+ TReg cell frequency in the
pancreatic lymph node and by modulating the balance of
cDC subsets towards CD8+ cDCs, which have potentially
tolerogenic functions60,61. of note, FlT3l treatment is pro-
tective only when administered in the early stages of T1D
development in NoD mice when islet antigen-specific
T cells are still at a low frequency 53. Thus, the opposing
role of FlT3l depends on the time of injection relative
to the disease progression in NoD mice. A recent study
highlighted the in vivo peripheral feedback loop that exists
between TReg cells and DC frequency involving FlT3l.
Deletion of TReg cells induced FlT3l production, which
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REVIEWS
Indoleamine
2,3-dioxygenase
(IDO). An intracellular
haem-containing enzyme
that catalyses the oxidative
catabolism of tryptophan.
IDO suppresses T cell
responses and promotes
immune tolerance in
mammalian pregnancy,
tumour resistance, chronic
infection, autoimmunity
and allergic inflammation.
Invariant NKT (iNKT) cells
Lymphocytes that express
a particular variable gene
segment, Vα14 (in mice) and
Vα24 (in humans), precisely
rearranged to a particular Jα
(joining) gene segment to yield
T cell receptor α-chains that
have an invariant sequence.
Typically, these cells
co-express cell surface
markers that are encoded by
the NK locus, and they are
activated by recognition of
CD1d, particularly when
α-galactosylceramide is
bound in the groove of CD1d.
506 | jUly 2010 | volUmE 10
increased DC frequency and subsequently restored the
normal TReg cell frequency required to prevent autoim-
mune diseases62. Importantly, G-CSF and FlT3l could
prevent T1D not only by increasing the numbers of cDCs
but also the numbers of pDCs.
Several molecules expressed by pDCs might be
involved in the induction of T cell tolerance, such as
PDl1, inducible T cell co-stimulator ligand (ICoSl) and
indoleamine 2,3-dioxygenase (IDo). A protective role for
pDCs in T1D was first described by Saxena et al.63: by
transferring naive BDC2.5 T cells to NoD-Scid mice,
they showed that pDCs inhibited the CD4+ T cell diabe-
togenic response, induced IDo in the pancreas and pre-
vented T1D onset. IDo catalyses oxidative catabolism of
tryptophan and, in this way, regulates T cell-mediated
immune responses, as free tryptophan is an essential
nutrient for T cells. Interestingly, a defect in IDo expres-
sion has been described in young NoD mice64, and over-
expression of IDo prolongs islet graft survival65. Using
both virus-induced and spontaneous models of T1D, we
recently observed that following viral infection, invariant
NKT (iNKT) cell–pDC crosstalk inhibits diabetogenic CTl
responses in the pancreas66. In this infectious context,
pDCs induced the conversion of CD4+ T cells to FoXP3+
TReg cells, which are crucial for preventing T1D (j.D. and
A.l., unpublished observations). Together, these studies
support a protective role of pDCs in T1D and strengthen
their potential use in new therapeutic strategies.
Protective role of NK cells in T1D. Despite their poten-
tial pathogenic role in T1D, several studies suggest a
protective function of NK cells. NK cells from the blood
of patients with T1D and lymphoid tissues from NoD
mice exhibit impaired function67–69. As this defect was
observed in patients with long-term T1D it could be a
consequence of the disease69. However, in NoD mice, the
NK cell defect is present before disease onset, suggesting
that impaired NK cell function could contribute to dis-
ease development 67,68. Consistent with this hypothesis,
injection of young NoD mice with complete Freund’s
adjuvant (CFA) induces IFNγ production by NK cells
and prevents T1D70. The protective role of NK cells in
this setting was shown by their ability to inhibit T1D
in transfer experiments. The beneficial role of NK cells in
islet allograft tolerance has been shown to involve killing
of DCs by NK cells in a perforin-dependent manner 71.
NK cells seem to have a protective role following CFA
immunostimulation of young NoD mice and in islet
allografts, whereas they have a deleterious effect in older
NoD mice that have massive islet infiltrates or in more
aggressive mouse models of T1D.
iNKT cells. iNKT cells are innate-like T cells that express
an invariant TCR α-chain (vα14–jα18 in mice and
vα24–jα18 in humans). Following activation, iNKT cells
promptly produce large amounts of various cytokines and
chemokines, thereby providing signals to other immune
cells, including DCs, NK cells and lymphocytes. Although
iNKT cells can promote immunity to pathogens, many
studies have shown their role in preventing auto-
immune diseases, particularly T1D (reviewed in ReF. 72).
© 2010 Macmillan Publishers Limited. All rights reserved
Increasing the frequency of iNKT cells, either by adop-
tive transfer or through the introduction of a vα14–jα18
transgene, substantially reduces the incidence of T1D in
NoD mice73,74. A similar protective effect was observed
after specific iNKT cell stimulation with the exogenous
ligand α-galactosylceramide or its analogues75–78. Early
reports suggested that iNKT cell-mediated protection
was associated with the induction of TH2 cell responses
to islet autoantigens75,76,79. However, studies using the
transfer of islet antigen-specific CD4+ and CD8+ T cells
showed that iNKT cells inhibit the differentiation of
these T cells into effector T cells during their priming
in the pancreatic lymph node80,81. Interestingly, these
islet antigen-specific CD4+ T cells became anergic and
remained in the pancreatic lymph node and pancreas80
where they could have a regulatory role. The abortive
priming of islet antigen-specific T cells in the pancreatic
lymph node could be explained by their ability to recruit
tolerogenic DCs81. Interestingly, type 2 NKT cells, which
express variable TCRs, can also prevent T1D in NoD
mice, although the precise mechanism is still under
investigation82. Although the number and function of
iNKT cells from NoD mice are defective, which could
contribute to T1D susceptibility 67,83, there is no consen-
sus on whether iNKT cell defects occur in humans with
T1D84,85. However, manipulations of iNKT cells prevent
and even cure T1D in various mouse models, encour-
aging the development of new therapeutic strategies to
target iNKT cells.
The dual role of DCs and NK cells in the development
of T1D could depend on different parameters: first, the
type of cell subsets involved (for example CD8– cDCs,
CD8+ cDCs and/or pDCs); second, different pathways
of activation through surface and cytoplasmic recep-
tors (such as TlR-mediated recognition of endogenous
and exogenous ligands); third, a pro-inflammatory or
regulatory cytokine milieu; and fourth, genetic defects
such as increased Il-12p40 production by DCs and
impaired NK cell function in NoD mice. The integra-
tion of all of these parameters could result in prevention
or exacerbation of T1D development by DCs and NK
cells. Interestingly, based on studies of mouse models,
these innate cells often seem to have a protective role
in the early phases of the disease, whereas increasing
their frequency or activating them at later stages, when
diabetogenic T cell frequency have reached a certain
threshold, may precipitate disease.
Infection and T1D
Potentiating disease. The previous section describes the
innate cells involved in the regulation of T1D, and DCs
have a pivotal role both in inducing and preventing dis-
ease, depending on various factors. As these cells express
several pathogen recognition receptors (PRRs) to sense
microorganisms, it is not surprising that infections can
modulate DCs, and other innate immune cells, and influ-
ence islet antigen-specific T cell responses and the devel-
opment of T1D (FIG. 3). TlR3 and the cytoplasmic proteins
retinoic acid-inducible gene-I (RIG-I) and melanoma
differentiation-associated gene 5 (mDA5; also known
as IFIH1) have been identified as crucial intracellular
www.nature.com/reviews/immunol
 REVIEWS

Virus Picornavirus encephalomyocarditis virus (EmCv)

Cytoplasmic induces T1D in wild-type mice. Infection with a high
Molecular
PRR dose of the D strain of EmCv results in acute onset
mimicry of T1D in more than 90% of infected animals within
Viral molecule 4 days of infection88. T1D onset in EmCv-infected mice
Viral antigen MHC cDC seemed to depend on macrophages but not T cells, as
TCR shown by blocking and depleting antibody treatments89.
Recruitment The mechanism of β-cell destruction by macrophages
Islet antigen- Inflammatory could be mediated through the release of cytokines
specific T cell molecules (TNF) and RoS89,90. Interestingly, fulminant T1D in
NK cell humans is associated with a macrophage-dominant,
Macrophage
NKG2D
rather than T cell-dominant, infiltrate91. These data show
the role of innate immune cell activation following virus
RAE1
infection in promoting T1D. In most examples in which
viruses induce T1D, infections lead to a cascade of innate
and adaptive immune cell activation with a clear role for
TGFβ Cytotoxicity β-cell diabetogenic T cells (as described below).
IL-10 IFNα

β-cell Cell death
antigen
TReg cell
TReg cell
induction by
tolerogenic DC
TCR
Viral or self antigen
MHC
Tolerogenic
cDC
iNKT cell
Figure 3 | Effects of viral infection on the regulation of type 1 diabetes. Infection
of the pancreas by viruses triggers the activation and recruitment
NatureofReviews
innate immune
| Immunology
such as macrophages, dendritic cells (DCs) and natural killer (NK) cells, which produce
pro-inflammatory cytokines through cytoplasmic pattern recognition receptor (PRR)
activation. In parallel, viruses can enhance the release of β-cell antigens through direct or
indirect β-cell damage. Activated antigen-presenting cells can present either self
antigen or viral antigens (in the case of molecular mimicry) to islet antigen-specific
T cells. The pro-inflammatory milieu created by the innate immune cells promotes the
recruitment and activation of islet antigen-specific T cells in the pancreas. Viral infection
can be controlled by invariant NKT (iNKT) cell–plasmacytoid DC (pDC) crosstalk leading
to a rapid elimination of the virus from the pancreas. In a second step, activated
tolerogenic conventional DCs (cDCs) and pDCs loaded with viral and/or self antigens
can induce regulatory T (TReg) cells, which mediate bystander suppression, through
transforming growth factor-β (TGFβ) and interleukin-10 (IL-10). The complex interplay
between viruses and immune cells reflects the dual role, beneficial or detrimental, of
infections in the development of type 1 diabetes. IFN, interferon; NKG2D, natural killer
group 2, member D; RAE1, retinoic acid early transcript 1; TCR, T cell receptor.
Stimulation of
Activation of autoimmune T cells through molecular
antiviral innate mimicry. Cross-reactive immune responses arising
immunity and through regions of sequence similarity between viral-
viral clearance and self-antigen epitopes could theoretically lead to
diabetogenic T cell activation and tissue destruction
following viral infection. Numerous mimics between
pDC
β-cell antigens and viral epitopes have been identified,
including coxsackie virus B4 (ReF. 92), rotavirus93, rubella
virus94 and Cmv95. The RIP–lCmv mouse model,
OX40–OX40L
which is based on transgenic expression of virus anti-
gens in β-cells, has been extensively used to investigate
mechanisms that could be involved in virus-induced
T1D and how self tolerance could be broken96,97. These
mice seemed to be tolerant of viral antigen, as no sponta-
neous T1D developed. However, following lCmv infec-
tion all of the transgenic mice became diabetic within a
cells
few weeks owing to the destruction of pancreatic β-cells
by virus-specific CTls. These virus-induced T1D mod-
els have help to reveal the key role for cytokines and
chemokines, produced by immune cells and even the
β-cells themselves, in the development of T1D. Blocking
or depletion of IFNγ, TNF or CXC-chemokine ligand 10
(CXCl10) reduced T1D incidence in these mice follow-
ing infection, revealing the crucial role for the inflam-
matory milieu in the development of virus-induced
T1D98–100. These studies show that viral infections could
induce T1D possibly by the activation of diabetogenic
T cells that are cross-reactive for both viral and self anti-
gen, but more importantly they show that viruses can
induce T1D by creating an inflammatory environment
favourable for diabetogenic T cell activation.

Molecular mimicry
Resemblance between epitopes
contained in microbial and host
proteins, leading to cross-
reactivity of T cells in the host.
Insulitis
An infiltration of lymphocytes
into pancreatic islets during the
progression of type 1 diabetes.
Insulitis can be innocuous or
destructive.
receptors for host responses to viral dsRNA86. Several
studies have suggested a genetic association between
mDA5 allelic variants and susceptibility to T1D 87.
Different viruses can induce or promote T1D through
various mechanisms, including molecular mimicry, induc-
tion of bystander damage of β-cells, release of sequestered
antigens and changes in the balance between the num-
bers of TReg cells and effector T cells (TABLe 1). There is
some evidence that viruses can directly destroy pancreatic
β-cells but in many cases there seems to be a requirement
for immune cells in the β-cell destruction process.
Activation of diabetogenic T cells through bystander
damage. The bystander damage resulting from virus
infection could involve nonspecific activation of auto-
immune cells by a pro-inflammatory milieu and/or
T cell activation through exposure to released islet
antigens. The association of bystander damage with
T1D onset was first revealed after coxsackie virus B4
infection of BDC2.5 TCR-transgenic NoD mice, which
induced rapid T1D101. T cells in these mice express a
TCR specific for a pancreatic antigen but interestingly,
these mice have a lower incidence of T1D and develop

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© 2010 Macmillan Publishers Limited. All rights reserved

REVIEWS

Table 1 | Infections associated with the regulation of type 1 diabetes

Pathogen Effect on mechanisms of action Refs
type 1 diabetes
Viral infections
Coxsackie B3 and B4 viruses Acceleration Bystander damage, release of sequestered antigens and molecular mimicry 92,101,
104–107,
Prevention Upregulation of PDL1 expression and TReg cell-mediated control of
110,111,132
diabetogenic CTL expansion
Cytomegalovirus Acceleration Molecular mimicry and congenital infections 95,133
Encephalomyocarditis virus Acceleration Direct destruction 88–90
Mumps virus Acceleration Unknown 9
Parvovirus Acceleration Change in TReg cell and effector T cell balance 133,134
Rhesus monkey rotavirus Acceleration Acceleration by induction of pro-inflammatory cytokines 108,109
Prevention Prevention mechanism unknown
Rubella virus Acceleration Molecular mimicry and congenital infections 94
Lymphocytic choriomeningitis virus Prevention Upregulation of PDL1 expression and TReg cell-mediated control of 111,135
diabetogenic CTL expansion
Lactate dehydrogenase virus Prevention Unknown (possible role for antigen-presenting macrophages) 136
Mouse hepatitis virus Prevention Unknown (only observational) 137
Murine gammaherpes virus-68 Delay Alteration of self-antigen presentation by DCs 138
Viral antigens
CpG DNA Prevention Decrease in T cell proliferative responses and possible shift to TH2 cell responses 116
CpG DNA No effect Not applicable 115
PolyI:C Prevention Expression of type I IFNs and induction of suppressor T cells 114
Bacterial infections
Salmonella enterica subsp. enterica Prevention TH1 cell- and IFNγ-mediated inhibition of type 1 diabetes and phenotypic 123,124*
serovar Typhimurium changes in DCs and IDO production
Mycobacterium avium Prevention Induction of suppressor T cells 139
Bacterial antigens
Mycobacterium bovis bacille Prevention Unknown (only observational) 120,121
Calmette–Guérin
Complete Freund’s adjuvant Prevention Expansion of natural suppressor cells and NK cells 70,122
(Mycobacteria)
Streptococcal OK-432 Prevention Unknown (only observational) 140
Klebsiella pneumoniae glycoprotein Prevention Expansion of natural suppressor cells 126
extract and Escherichia coli LPS
OM-85 (complex mix of bacterial Prevention Induction of TGFβ, TReg cells and NKT cells 141
extracts)
Fungal antigens
Zymosan Prevention Activation of innate cells, TReg cells 127
Helminth infections
Schistosoma mansoni Prevention Shift to TH2-type response 130
Trichinella spiralis Prevention Shift to TH2-type response 142
Heligmosomoides polygyrus Prevention Shift to TH2-type response 142
Litomosoides sigmodontis Prevention Shift to TH2-type response and TReg cell increase 143
Helminth antigens
L. sigmodontis antigen Prevention Shift to TH2-type response and TReg cell increase 143
Dirofilaria immitis IgE-inducing antigen Prevention Shift to TH2-type response 144
S. mansoni soluble worm antigen or Prevention Expansion of alternatively activated macrophages, tolerogenic DCs and 128,129,
soluble egg antigen iNKT cells, TH2 cells and TReg cells 131
S. mansoni eggs Prevention Induction of TH2 cells 130
APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; IFN, interferon; IDO, indoleamine 2,3-dioxygenase; LPS, lipopolysaccharide;
NK, natural killer; PDL1, programmed cell death ligand 1; polyI:C, polyinosinic–polycytidylic acid; TGFβ, transforming-growth factor-β; TH, T helper; TReg, regulatory T.
*Also observed by S. Newland and A.C., unpublished observations.

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© 2010 Macmillan Publishers Limited. All rights reserved


non-invasive insulitis102,103. Coxsackie virus B4 infec-
tion of NoD mice also led to the acceleration of T1D
development but only in mice at least 8 weeks of age
with a pancreatic infiltrate of islet antigen-specific
T cells; younger mice were resistant to the disease104.
In the NoD mouse model, an accumulation of a crucial
number of islet antigen-specific T cells was required for
the induction of T1D by coxsackie virus B4 and other
coxsackie virus B strains105. Treatment with the TlR3
ligand polyinosinic–polycytidylic acid (polyI:C), a syn-
thetic double-stranded RNA that induces the secretion
of large amounts of IFNα by DCs and macrophages, is
not sufficient to induce T1D in BDC2.5 TCR-transgenic
NoD mice106. These results suggest that nonspecific acti-
vation of T cells mediated by virus-induced inflammatory
cytokines is not sufficient to induce disease.
Coxsackie virus B4-specific innate immune
responses result in pancreatic tissue damage and the
capture of released self antigens by APCs. Coxsackie
virus B4 did not induce direct β-cells death after infec-
tion; it triggered the upregulation of cell surface mark-
ers on β-cells associated with cellular stress, particularly
death receptor 4, and subsequent engulfment of infected
islets by macrophages107. These macrophages induced
T1D following transfer into uninfected BDC2.5 TCR-
transgenic NoD mice, showing their involvement in the
induction of T1D following viral infection. Therefore,
viral infection could have a role in T1D development by
potentiating ongoing autoimmune disease through the
induction of inflammatory cytokines and the stimula-
tion of self-antigen-presenting APCs.
Inhibiting disease. Although some viruses have been
shown to promote T1D pathogenesis, infections have also
been shown to have a protective role in T1D (TABLe 1). This
dual role of viruses in T1D depends on the different effects
that the virus might have on β-cells or in the modulation
of molecules and cells involved in controlling T1D.
An example of the dual role of a virus in T1D is the
rhesus monkey rotavirus (RRv), which provides protec-
tion when inoculated into young NoD mice but exac-
erbates disease if administered when insulitis is already
established108,109. Similar effects on T1D development are
observed with coxsackie virus infection of NoD mice. In
this case, the virus precipitates disease after a crucial level
of islet antigen-specific immune cells has accumulated in
the pancreas, but can also prevent T1D in pre-diabetic
NoD mice110. Coxsackie viruses can control the expan-
sion of islet antigen-specific CTls by upregulating PDl1
expression on lymphocytes. As the interaction between
PD1 and PDl1 is known to control not only T cell
immunity to viral infection but also autoimmune
T cell responses, the hypothesis that viral infection can
potentiate regulatory mechanisms is consistent with
the protective effects observed on T1D development.
Increased numbers of CD4+CD25+ TReg cells are also
observed in coxsackie virus infection111. TReg cells from
infected NoD mice express high levels of TGFβ, CTlA4
and glucocorticoid-induced TNF-receptor-related
protein (GITR), and have increased ability to regulate
the onset of T1D during the pre-diabetic phase, when
NATURE REvIEwS | Immunology
© 2010 Macmillan Publishers Limited. All rights reserved
REVIEWS
compared with naive TReg cells from uninfected mice.
Positive correlations have been observed between lCmv
infection and PDl1 upregulation, enhanced TReg cell
number and tolerogenic function following infection111. It
would be interesting to determine whether viral infections
upregulate PDl1 expression on β-cells, which is already
expressed in uninfected NoD mice and participates in the
control of diabetogenic T cell attack112.
The use of RIP–lCmv model has enabled the
identification of a new immune cell crosstalk that con-
trols pancreatic viral load and thereby T1D onset 66,113.
Following infection with lCmv, iNKT cells promote
pDCs recruitment into the pancreas and their produc-
tion of type I IFNs. This local iNKT–pDC crosstalk is
dependent on the oX40–oX40l pathway. iNKT cells in
the pancreas, but not in lymphoid tissues, express oX40,
and experiments with blocking antibodies, as well as
the transfer of wild-type iNKT cells to oX40-deficient
mice, have shown the crucial role of oX40–oX40l in
the iNKT cell–pDC interaction. As a result, in the pan-
creas (but not in the spleen), iNKT cells enhance IFNα
production by pDCs and inhibit local viral replication.
The low viral burden in the pancreas results in a weak
local adaptive immune response, thereby preventing tis-
sue damage and T1D development. These results reveal
that the diabetogenic effect of lCmv can be controlled
by efficient innate immune cell crosstalk, limiting the
activation of diabetogenic T cells.
viral antigens in the absence of infection also prevent
diabetes in NoD mice. For example, polyI:C can pro-
tect NoD mice from developing T1D114 and, although
controversial115, vaccination using CpG-containing
oligodeoxynucleotides (which are TlR9 ligands) also
inhibited T1D development in NoD mice116. Recent
data from the streptozotocin model of T1D suggest that
TlR9 agonists might inhibit diabetes onset through the
induction of IDo expression by DCs117. TlR3 and TlR9
are expressed not only by cells of the immune system but
also by β-cells118, raising the possibility that these TlR
ligands function at several levels.
There are many studies showing reduced insulitis
and inhibition of T1D development following expo-
sure of NoD mice to mycobacterial species or anti-
gens119–122 and Salmonella enterica subsp. enterica serovar
Typhimurium123. Given that T1D is a TH1 cell-mediated
disease, this is intriguing as both infections are known
to activate macrophages and DCs that induce a typical
TH1 cell-mediated immune response. S. Typhimurium
infection prevents T1D in NoD mice with an already
established infiltrate in the pancreas123. The transfer of
DC-enriched populations from S. Typhimurium-infected
mice to NoD mice injected with the chemotherapeutic
drug cyclophosphamide to accelerate T1D prevented dis-
ease development 124. In this model, the immunomodula-
tory effect was due to the ability of the transferred DCs to
prevent the trafficking of islet antigen-specific T cells into
the pancreas. The paradoxical protective effect of TH1
cell-inducing infections (and their antigens (TABLe 1)) on
a TH1 cell-mediated autoimmune disease indicates that
a classic pro-inflammatory immune response is not suf-
ficient to exacerbate disease per se. Intracellular infections
volUmE 10 | jUly 2010 | 509
REVIEWS
such as S. Typhimurium can induce the expression of
IFNγ, resulting in induction of anti-inflammatory mol-
ecules such as IDo, not just in lymphoid tissues but
also in the pancreas (S. Newland and A.C., unpublished
observations). IDo has been shown to be produced by
human pancreatic β-cells in response to IFNγ and its role
has been proposed as a self-defence mechanism against
inflammation125. Functional evidence of a tolerogenic
role of islet IDo in vivo has been shown by prolonged
survival of IDo-expressing islets following transplan-
tation65. Furthermore, an inverse correlation has been
observed between IDo and apoptosis, suggesting that
IDo may have an additional protective role by reducing
oxidation and mHC class I expression.
PRR ligands of either bacterial126 or fungal origin127
can also prevent diabetes in NoD mice. The fungal cell
wall component zymosan is recognized by innate
cells through an interaction with TlR2 and the C-type
lectin receptor dectin 1 (also known as ClEC7A).
Zymosan induces phenotypic changes in DCs and
macrophages, which results in the secretion of both
pro-inflammatory cytokines (Il-6 and TNF) and anti-
inflammatory cytokines (Il-10 and TGFβ)127. Zymosan
also upregulated the expression of Il-10 and TGFβ by
CD4+ T cells127. These changes seem to be involved in
the suppression of insulitis.
The expression of TlR2 and TlR4 by β-cells adds
another site at which these agents can potentially func-
tion118. Interestingly, it has been shown that gut microbi-
ota may have a crucial role in T1D development46. Studies
in myeloid differentiation primary-response protein 88
(myD88)-deficient NoD mice kept in germ-free con-
ditions have revealed normal disease development in
these mice, whereas a decreased incidence was observed
following gut colonization with commensal microorgan-
isms. This suggests that some organisms can prevent T1D
development in a myD88-independent manner but does
not exclude the involvement of other PRRs.
Perhaps less surprising, but also complex, is the effect
of parasitic infections on T1D. Parasitic worms (and
their products) can rapidly skew the immune response
of the host towards an anti-inflammatory response,
in order to secure their own survival. The common
immune response observed during helminth infection
(or immunization with parasite products) is character-
ized by the induction of an immature phenotype in DCs
and the alternative activation of macrophages128, as well
as TH2 and TReg cell129 development. Schistosoma mansoni
infection or injection of S. mansoni antigens dramatically
reduces T1D incidence in NoD mice130,131. After exposure
to S. mansoni soluble egg antigen (SEA), for example, the
composition of the cellular infiltrate in the pancreas of
NoD mice is markedly changed. In particular, there is
increased expression of FoXP3, Il-4, Il-10 and TGFβ
by CD4+ T cells128,129. The number of iNKT cells is also
increased in NoD mice exposed to SEA131. Thus in
the context of a live infection with S. mansoni, several
different cell types of both the innate and the adaptive
immune responses are affected with the potential to
influence each other and reinforce their ability to inhibit
autoimmune pathology.
510 | jUly 2010 | volUmE 10
© 2010 Macmillan Publishers Limited. All rights reserved
Pathogens such as parasites and bacteria are usu-
ally protective against T1D, whereas viruses have a dual
role. The ability of viruses to induce or promote T1D can
depend on a susceptible genetic background, the tro-
pism of the virus for islet cells and its ability to induce a
strong pro-inflammatory response10. Conversely, virus
infection in the presence of a limited number or absence
of diabetogenic T cells is usually beneficial against T1D.
The local pancreatic viral load is a crucial parameter and,
therefore, the efficiency of immune cell crosstalk con-
trolling viral replication, subsequent β-cell damage and
pro-inflammatory cytokine secretion will determine the
outcome of the infection on T1D.
Concluding remarks and future directions
Studies of the pathogenesis of T1D have largely focused
on the analysis of diabetogenic T cells and their control
by TReg cells. However, there is increasing evidence that
innate immune cells have crucial roles in T1D patho-
genesis. Innate cells such as macrophages, DCs and NK
cells are required for the development of T1D in vari-
ous mouse models and these cells have been detected
in the pancreas of patients with T1D. Innate cells such
as DCs, NK and iNKT cells have also been shown to be
involved in protection against this disease. This Review
highlights the potential for the ambivalent function of
innate immune cells in T1D. many observations sup-
port a protective role for these cells following their
activation, by specific agonist or following microbial
infection, in younger mice harbouring limited β-cell
destruction and diabetogenic T cell frequency. one of
the key questions that remain to be addressed is why
these innate immune cells are inefficient in preventing
T1D in the absence of exogenous triggering but instead
participate in the development of the disease. one
hypothesis is that T1D could be associated with some
immune deficiency of innate immune cells render-
ing them unable to induce tolerance to islet antigens,
whereas chronic low activation of these cells through
continued β-cell death and/or persistent virus activates
their pathogenic functions.
The knowledge gained from the analysis of the pre-
ventative mechanisms induced by some infections sug-
gests two main pathways for the development of new
therapeutic approaches for T1D. The first could be
based on parasite or bacterial components that are pro-
tective in mouse models of T1D or in other immune-
mediated pathologies in humans such as inflammatory
bowel disease and asthma. The second could focus on
specific triggering of innate cells, such as pDCs and
NKT cells, that preferentially exert a protective role
against T1D. However, as pDCs can also have delete-
rious effects, similar to cDCs, their triggering by PRR
ligands should be restricted to individuals at risk but
still devoid of any sign of islet-specific autoimmunity,
as indicated by the presence of specific autoantibodies
and islet antigen-specific T cells. Concerning the exog-
enous activation of iNKT cells, many investigations are
currently underway to generate and screen new agonists
to obtain molecules that preferentially direct NKT cells
towards regulatory pathways.
www.nature.com/reviews/immunol

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Acknowledgements
We apologize to all the authors whose work we could not cite
owing to space constrictions. The Cooke laboratory is sup-
ported by The Wellcome Trust, Medical Research Council
(MRC) and Diabetes UK. P.Z. is supported by the MRC. The
Lehuen laboratory is supported by the Institut National de la
Santé et de la Recherche Médicale (INSERM), Agence
Nationale de la Recherche (ANR-GENOPAT) and the European
Foundation for the Study of Diabetes (EFSD).
Competing interests statement
The authors declare no competing financial interests.
DATABASES
UniProtKB: http://www.uniprot.org
dectin 1 | FLT3L | ICOSL | IDO | IFNγ | IL-1β | KLRG1 | MDA5 |
NKG2D | PD1 | PDL1 | RIG-I | TLR2 | TLR3 | TLR7 | TLR9 | TNF
FURTHER INFORMATION
Anne Cooke’s homepage: http://www.path.cam.ac.uk/
research/investigators/cooke/
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