Regulatory T cells

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