ICI Basic Immunology course

Effector mechanisms of
cell-mediated immunity:
Properties of effector,
memory and regulatory T cells

Abul K. Abbas, MD
UCSF
Stages in the development of T cell responses: induction
Stages in the development of T cell responses:
effector phase
 Kinetics of a T cell response

From: Abbas & Lichtman, Cellular & Molecular Immunology, W. B. Saunders, 2003
 Clonal expansion of T cells

Stimulated mainly by autocrine IL-2

T cell stimulation by antigen + costimulators induces secretion
of IL-2 and expression of high-affinity IL-2 receptors
Therefore, antigen-stimulated T cells are the ones that
expand preferentially in any immune response
CD8+ T cells may expand >50,000-fold within a week
after an acute viral infection
Minimal expansion of cells not specific for the virus (up to
10% of all CD8+ T cells in the blood may be specific for the
pathogen)

Some of the progeny of the expanded clone

differentiate into effector and memory cells; the
majority die by apoptosis
 Roles of cytokines in T cell
maintenance
Nave T cells: IL-7

Recently activated T cells: IL-2

Memory T cells:
CD8: IL-7; IL-15
CD4: IL-7
Heterogeneity of differentiated
CD4+ effector T cells

Under different
activation conditions,
CD4+ helper T cells
can differentiate into
subpopulations that
make different cytokines
and perform different
functions
Signature cytokines:
TH1 cells: IFN-!
TH2 cells: IL-4, IL-5,
IL-13
Properties of Th1 and Th2 subsets

From: Abbas & Lichtman, Cellular & Molecular Immunology, W. B. Saunders, 2003
Functions of Th1 cells

The signature cytokine

of Th1 cells is IFN-!.
Th1 cells combat cell-
associated microbes (most
bacteria and viruses that
are seen by dendritic
cells and macrophages)
Development of Th1 cells

Th1 cells develop in

response to microbes
that activate dendritic
cells and macrophages
(most bacteria and
viruses).
Transcription factors:
IFN-! --> T-bet
IL-12 --> Stat4
Functions of Th2 cells

The signature cytokines

of Th2 cells are IL-4,
IL-5 and IL-13.
Th2 cells combat
helminths, provide
defense at mucosal
barriers (barrier
immunity), and are
involved in allergic
reactions.
Development of Th2 cells

Th2 cells develop in response

to organisms that usually
do not activate macrophages
and dendritic cells strongly.
Transcription factors:
TCR? --> GATA-3
IL-4 --> Stat6
 Biology of Th1 and Th2 subsets

Effector CD4+ T cells that develop from nave

cells after activation

Th1: in response to most microbes that elicit

innate immunity; function in microbial
destruction by phagocytes and killing of
infected cells, tumors

Th2: in response to some parasites; function to

activate mast cells and eosinophils
 Effector mechanisms in immunity
and inflammatory diseases: the dogma
 Fates of CD4 T cells
Th1 cells (IFN-!):
Host defense,
inflammation

Th2 cells (IL-4, IL-5):

Host defense (helminths),
Activation allergic reactions

Nave CD4 Th17 cells (IL-17):

T cell Inflammatory
disorders

Regulatory T cells
 IL17-producing (Th17) cells

Involved in inflammatory diseases (MS,

IBD, RA, others): leukocyte recruitment
Defense against extracellular bacteria

Induced by cytokines:
TGF-" + IL-6 (other inflammatory cytokines)
--> IL-17; mainly IL-1 with human cells
(TGF-" alone --> regulatory T cells)
IL-23 enhances Th17 response
IL-21 amplifies the response
Inhibited by Th1 and Th2 cytokines
 Fates of CD4 T cells:
signals and transcription factors
Th17 cells (IL-17)

-6
IL
Th1 cells (IFN-!)

3?
+

at
"
F-

St
TG

t;!

-12
R-

IFN-!, IL
RO

T-bet, Stat4
IL-4
Nave CD4 GAT
A-3
T cell TG
, St
at6
F-
";
IL
Th2 cells (IL-4)
Fo
xP -2
3

Regulatory T cells
 Memory T cells

Long-lived, functionally silent, rapid recall

responses

Develop from antigen-stimulated T cells;

maintained by cytokines (IL-7, others)

May consist of multiple subsets (central

and effector)
Differ in localization (lymphoid tissues vs non-
lymphoid peripheral tissues) and functions
 Central and effector memory cells
Central memory cells:
L-selectin-high, CCR7-high; may migrate to lymph
nodes
Proliferate, do not produce effector cytokines
Pool of cells available for secondary response

Effector memory cells:

CCR7-low, L-selectin variable; may migrate to
peripheral (non-lymphoid?) tissues, e.g. mucosa
Produce effector cytokines; mediate rapid
cytotoxicity (CD8)
Perform effector function of eliminating microbes
 Regulatory T cells

From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007
 Regulatory T cells
Regulatory T cells are CD4+ cells that
express high levels of CD25 and FoxP3
Generated by self antigen recognition in the
thymus or peripheral tissues
Generation requires the transcription factor
Foxp3
Mechanism of action: inhibitory cytokines;
contact-mediated inhibition of dendritic cells,
responding T cells?
Significance:
Reported deficiencies in autoimmune diseases
Therapeutic potential (cellular therapy)
 Fates of immature T cells that
recognize self antigens in the thymus
 Regulatory T cells: some of the
knowns and unknowns
Induction requires TGF-" --> Foxp3 -->
complex transcriptional program
TGF-" and Foxp3 are necessary but may not be
sufficient
Source of TGF-" in thymus and periphery (T cells
themselves, APCs)?
Induction counteracted by inflammatory signals (e.g.
IL-6)

Reliable markers?

Heterogeneity of regulatory populations?

 The unexpected biology of IL-2

Interleukin-2 is the prototypic T cell

growth factor (TCGF), required for
initiating clonal expansion of T cells in
response to antigen

BUT: knockout of IL-2 or the # or "

chain of the IL-2R results not in immune
deficiency but in systemic autoimmunity
and lymphoproliferation
 Dual roles of IL-2 in T cell responses

The obligatory (non-redundant) function of IL-2 is to maintain

functional regulatory T cells (thus to control lymphocyte activation)
The dichotomy of memory and regulatory T cells

Memory T cells
Strong stimuli
(e.g. pathogens)
IL-2R-low
Nave IL-7R++
T cell Depend on IL-7

Regulatory T cells
Weak stimuli
(e.g. self antigen)
IL-2R++
IL-7R-low
Depend on IL-2
 Clinical implications of the dual
function of IL-2
Will IL-2 therapy, e.g. to boost immune
responses against cancers, result in more
Treg and immune suppression?
Will IL-2 antagonists, e.g. for GvHD,
graft rejection, convert an acute self-
limited disease to a chronic disease?

Ways of predicting the dominant effects

of IL-2 in vivo?
Therapeutic strategies: blocking T cell activation

Current strategies
target mechanisms
of normal lymphocyte
activation, and are
not specific for
abnormalities
associated with
immune-mediated
inflammatory diseases.
 T cell activation and regulation

Improving understanding of pathways of

T-cell responses and their control

Challenges:
Inherent complexity
Application to humans
Using emerging information for
developing new therapeutic strategies