Download Effector mechanisms of cell-mediated immunity:

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
• Naïve 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 cellassociated 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 naïve
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
Activation
Naïve CD4
T cell
Regulatory T cells
Th2 cells (IL-4, IL-5):
Host defense (helminths),
allergic reactions
Th17 cells (IL-17):
Inflammatory
disorders
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
Naïve CD4
T cell
St
at
3?
Th1 cells (IFN-!)
t;
RO
R!
TG
F"
+
IL
-6
Th17 cells (IL-17)
-12
IFN-!, IL
T-bet, Stat4
IL-4
GAT
A-3
, St
at6
TG
F";
IL
Fo
-2
xP
3
Th2 cells (IL-4)
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 nonlymphoid 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)
Naïve
T cell
IL-2R-low
IL-7R++
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 selflimited 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