T Cell Activation, Costimulation and Regulation

Transcription

1 1 T Cell Activation, Costimulation and Regulation Abul K. Abbas, MD University of California San Francisco 2 Lecture outline T cell antigen recognition and activation Costimulation, the B7:CD28 family Inhibitory receptors of T cells Memory T cells 1

2 Classes of T lymphocytes 3 Abbas, Lichtman and Pillai. Cellular and Molecular, 9 th edition, 2017 The life history of T lymphocytes 4 2

3 Steps in T cell activation 6 Signals for T cell activation Antigen recognition Costimulators (second signals) Cytokines Produced by s or T cells Stimulate T cell expansion and differentiation into effector cells 3

4 Recognition of a peptide-mhc complex by a T cell antigen receptor (TCR) 7 Staining antigen-specific T cells 8 Physiologic antigen recognition Peptide-MHC tetramer staining T cell T cell TCR MHC/peptide Biotin-MHC loaded with peptide Fluorescent streptavidin Limited to T cells of known MHC restriction Important for analyzing immune responses in humans Other methods: activate cells with multiple peptides 4

5 Molecules involved in T cell activation 9 Formation of the immunological synapse 10 Regulated way of bringing together key signaling molecules 5

6 Principal signaling pathways in T cell activation Membrane signal (TCR complex, other receptors) --> biochemical intermediates --> transcription factors 11 Calcium -- calcineurin --> NFAT Ras/MAP-kinase --> AP-1 PKC -- CARMA/BCL-10 --> NF B PI3-kinase -- Akt --> NF B Cytokines --> Jak-Stat Therapeutic targeting of molecules involved in T cell responses 12 CD3: signaling molecule attached to the TCR on all T cells; anti-cd3 MAb to deplete T cells (transplants) Integrins (LFA-1, VLA-4, others): adhesion to s, endothelium; antiintegrin antibodies to block leukocyte migration Costimulators: B7-CD28, others; costimulatory blockade 6

7 The two-signal requirement for lymphocyte activation 13 Second signals for T cells: costimulators induced on s by microbial products, during early innate response Second signals for B cells: products of complement activation recognized by B cell complement receptors Role of costimulation in T cell activation 14 7

8 15 Costimulation Stimulus in addition to antigen that is required for initiating T cell responses Ensures that T cells respond to microbes (the inducers of costimulators) and not to harmless antigens Source of costimulation during responses to tumors, transplants? Targets for therapeutic blockade of T cell responses The B7:CD28 families 16 8

9 Major functions of selected CD28:B7 family members 17 Activation CD28:B7: initiation of T cell responses ICOS:ICOS-L: T cell help in germinal center reactions (antibody responses) Inhibition CTLA4:B7: inhibits early T cell responses in lymphoid organs PD1:PD-L1,2: inhibits effector T cell responses in peripheral tissues Complexities and unknowns of B7:CD28 costimulation 18 Different T cell populations vary in their dependence on B7:CD28: Naïve > activated > memory CD4 > CD8 Regulatory T cells (controllers of immune responses) are also B7-dependent Redundancy of B7-1 and B7-2? Does B7 signal backwards into s? 9

10 19 Costimulators other than B7:CD28 Many proteins of the TNF-receptor family are expressed on T cells and implicated in T-cell activation and control Functions often demonstrated in complex experimental systems or in vitro Roles in disease (human or animal models) not definitely established Possible therapeutic targets? Therapeutics based on the B7:CD28/CTLA-4 family 1. Costimulatory blockade 20 CTLA-4.Ig inhibits T cell activation in diseases caused by T cell responses-- rheumatoid arthritis, kidney graft rejection 10

11 Inhibitory receptors of the immune system 21 One mechanism by which the system maintains a balance between activation and inhibition is to use different receptors for different outcomes Inhibitory receptors are present in NK cells, T cells and B cells; perhaps other immune cells? The opposing functions of CD28 and CTLA-4 22 B7 CD28 B7-CD28 interaction TCR CTLA-4 Naïve T cell Proliferation, differentiation B7-CTLA-4 interaction Functional inactivation Knockout of CTLA-4 in mice and mutation in humans results in immune dysregulation (lymphoproliferation, multi-organ inflammation) 11

12 Actions of CTLA-4 23 Immune response B7 CD28 TCR Naïve T cell Effector and memory T cells Expression of CTLA-4 CTLA-4 Responding T cell Cell-intrinsic: Termination of response Regulatory T cell Responding T cell Cell-extrinsic: Treg-mediated suppression of response CTLA-4 competitively inhibits B7-CD28 engagement 24 B7 CD28 T Cell Costimulation T cell activation 12

13 CTLA-4 competitively inhibits B7-CD28 engagement 25 B7 CD28 B7 CTLA-4 T Cell Costimulation T cell activation T cell (activated T cell or Treg) CTLA-4 blocks and removes B7 lack of costimulation T cell inhibition Consequence of mutations in the CTLA-4 pathway 26 B7 CD28 T Cell Unopposed costimulation Excessive T cell activation Therapy? 13

14 27 Functions of CTLA-4 Limits activation of responding T cells Mediates suppressive function of regulatory T cells (Tregs) How does the T cell choose to use CD28 to be activated (e.g. with microbes) or CTLA-4 to shut down (e.g. with self Ag)? Functions of CTLA-4 28 Limits activation of responding T cells Mediates suppressive function of regulatory T cells (Tregs) How does the T cell choose to use CD28 to be activated (e.g. with microbes) or CTLA-4 to shut down (e.g. with self Ag)? Level of B7 expression and affinity of receptors: Low B7 (e.g. when DC is displaying self antigen) - -> engagement of high-affinity CTLA-4; High B7 (e.g. after microbe encounter) --> engagement of lower affinity CD28 14

15 29 The PD-1 inhibitory pathway PD-1 recognizes two widely expressed ligands (PD-L1, PD-L2) Knockout of PD-1 leads to autoimmune disease (less severe than CTLA-4-KO) Role of PD-1 in T cell suppression in chronic infections, tumors? 30 Action of PD-1 Normal response PD-1 engagement 15

16 T cell exhaustion in chronic viral infections 31 Naïve CD8+ T cells Virus Effector T cells Acute infection: clearance of virus Chronic infection: persistence of virus Memory T cells: enhanced antiviral responses Exhausted T cells: inability to respond to virus (expression of inhibitory receptors, e.g. PD-1, others) 32 Functions of CTLA-4 and PD-1 CTLA-4 PD-1 Major site of action Lymphoid organs Peripheral tissues Stage of immune Induction Effector phase response suppressed Mechanism of action Competitive inhibitor Signaling inhibitor of CD28 of CD28 and TCR Cell type suppressed CD4+ and CD8+ CD8+ > CD4+ 16

17 T cell activating and inhibitory receptors 33 Inhibitory receptors CTLA-4 PD-1 TIM-3 Activating receptors (costimulators) CD28 ICOS OX40 T cell TCR TIGIT LAG-3 BTLA CD27 GITR CD137 (4-1BB) T cell expansion and contraction (decline) 34 Many aspects of T cell responses and functions are mediated by cytokines: initial activation -- IL-2; maintenance of memory cells -- IL-7; effector functions -- various 17

18 Stages in the life history of lymphocytes 35 Accumulation of memory T cells with age 36 18

19 37 Memory T cell heterogeneity Central memory T cells Live in lymphoid organs, proliferate in response to antigen provides pool of effector cells for secondary response Effector memory T cells Present in tissues, rapid effector response Tissue-resident memory T cells (Trm) Long-lived in tissues 19