ICI Basic Immunology course

Effector mechanisms of cell-mediated immunity:

Properties of effector, memory and regulatory T cells

Abul K. Abbas, MDUCSF

Stages in the development of T cell responses: induction

Stages in the development of T cell responses: effector phase

From: Abbas & Lichtman, Cellular & Molecular Immunology, W. B. Saunders, 2003

Kinetics of a T cell response

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 thatexpand preferentially in any immune response

• CD8+ T cells may expand >50,000-fold within a weekafter 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 thepathogen)

• Some of the progeny of the expanded clonedifferentiate into effector and memory cells; themajority die by apoptosis

Roles of cytokines in T cellmaintenance

• 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 functionsSignature cytokines: TH1 cells: IFN-! TH2 cells: IL-4, IL-5, IL-13

From: Abbas & Lichtman, Cellular & Molecular Immunology, W. B. Saunders, 2003

Properties of Th1 and Th2 subsets

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.

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

Development of Th2 cells

Biology of Th1 and Th2 subsets

• Effector CD4+ T cells that develop from naïvecells after activation

• Th1: in response to most microbes that elicitinnate immunity; function in microbialdestruction by phagocytes and killing ofinfected cells, tumors

• Th2: in response to some parasites; function toactivate mast cells and eosinophils

Effector mechanisms in immunity and inflammatory diseases: the dogma

Th1 cells (IFN-!):Host defense, inflammation

Th2 cells (IL-4, IL-5):Host defense (helminths), allergic reactions

Th17 cells (IL-17):Inflammatory disorders

Naïve CD4T cell

Activation

Fates of CD4 T cells

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

Th1 cells (IFN-!)

Th17 cells (IL-17)

Naïve CD4T cell

Regulatory T cells

IFN-!, IL-12

T-bet, Stat4

TGF-" + IL-6

ROR-!t; Stat3?

TGF-"; IL-2FoxP3

Th2 cells (IL-4)

IL-4GATA-3, Stat6

Fates of CD4 T cells: signals and transcription factors

Memory T cells

• Long-lived, functionally silent, rapid recallresponses

• Develop from antigen-stimulated T cells;maintained by cytokines (IL-7, others)

• May consist of multiple subsets (centraland 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 rapidcytotoxicity (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 thatexpress high levels of CD25 and FoxP3– Generated by self antigen recognition in the

thymus or peripheral tissues

– Generation requires the transcription factorFoxp3

• 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 thatrecognize self antigens in the thymus

Regulatory T cells: some of theknowns 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 cellgrowth factor (TCGF), required forinitiating clonal expansion of T cells inresponse to antigen

• BUT: knockout of IL-2 or the # or "chain of the IL-2R results not in immunedeficiency but in systemic autoimmunityand 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)

Regulatory T cells

Naïve T cell

Memory T cells

Weak stimuli (e.g. self antigen)

Strong stimuli (e.g. pathogens)

IL-2R-lowIL-7R++

Depend on IL-7

IL-2R++IL-7R-low

Depend on IL-2

The dichotomy of memory and regulatory T cells

Clinical implications of the dualfunction of IL-2

• Will IL-2 therapy, e.g. to boost immuneresponses against cancers, result in moreTreg 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 effectsof IL-2 in vivo?

Therapeutic strategies: blocking T cell activation

Current strategiestarget mechanismsof normal lymphocyteactivation, and arenot specific forabnormalitiesassociated withimmune-mediatedinflammatory diseases.

T cell activation and regulation

• Improving understanding of pathways ofT-cell responses and their control

• Challenges:

– Inherent complexity

– Application to humans

– Using emerging information fordeveloping new therapeutic strategies