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Home , Memory T cell, T cell

2018 Advanced Course in Basic & Clinical February 19, 2018

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T Cell Activation, Costimulation and Regulation

Abul K. Abbas, MD University of California San Francisco

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Lecture outline

• recognition and activation

• Costimulation, the :CD28 family

• Inhibitory receptors of T cells

• Memory T cells

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Classes of T 3

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 9th edition, 2017

4 The life history of T lymphocytes

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Steps in T cell activation

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Signals for T cell activation

• Antigen recognition

• Costimulators (second signals)

• – Produced by APCs or T cells – Stimulate T cell expansion and differentiation into effector cells

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Recognition of a -MHC complex by a T 7 cell antigen (TCR)

Staining antigen-specific T cells 8

Physiologic Peptide-MHC antigen recognition tetramer staining

T cell T cell

TCR

MHC/peptide Biotin-MHC loaded with peptide APC Fluorescent streptavidin

Limited to T cells of known MHC restriction Important for analyzing immune responses in humans Other methods: activate cells with multiple

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9 Molecules involved in T cell activation

Formation of the 10

Regulated way of bringing together key signaling molecules

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11 Principal signaling pathways in T cell activation • Membrane signal (TCR complex, other receptors) --> biochemical intermediates --> factors

• Calcium -- --> NFAT • Ras/MAP-kinase --> AP-1 • PKC -- CARMA/BCL-10 --> NFB • PI3-kinase -- Akt --> NFB

• Cytokines --> Jak-Stat

12 Therapeutic targeting of molecules involved in T cell responses

• CD3: signaling molecule attached to the TCR on all T cells; anti-CD3 MAb to deplete T cells (transplants)

• (LFA-1, VLA-4, others): adhesion to APCs, endothelium; anti- to block leukocyte migration

• Costimulators: B7-CD28, others; costimulatory blockade

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13 The two-signal requirement for activation

Second signals for T cells: “costimulators” induced on APCs by microbial products, during early innate response

Second signals for B cells: products of complement activation recognized by complement receptors

14 Role of costimulation in T cell activation

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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 – Source of costimulation during responses to tumors, transplants?

• Targets for therapeutic blockade of T cell responses

16 The B7:CD28 families

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17 Major functions of selected CD28:B7 family members • CD28:B7: initiation of T cell responses • ICOS:ICOS-L: T cell help in reactions ( Activation responses)

• CTLA4:B7: inhibits early T cell responses in lymphoid organs • PD1:PD-,2: inhibits effector T

Inhibition cell responses in peripheral tissues

18 Complexities and unknowns of B7:CD28 costimulation

• 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 APCs?

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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?

20 Therapeutics based on the B7:CD28/CTLA-4 family 1. Costimulatory blockade

CTLA-4.Ig inhibits T cell activation in diseases caused by T cell responses-- , kidney graft rejection

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21 Inhibitory receptors of the

• 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?

22 The opposing functions of CD28 and CTLA-4

B7 CD28 B7-CD28 interaction APC Naïve TCR T cell Proliferation, differentiation CTLA-4 B7-CTLA-4 interaction Functional inactivation

Knockout of CTLA-4 in mice and mutation in humans results in (lymphoproliferation, multi-organ )

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Actions of CTLA-4 23 CD28 B7 TCR Effector and APC memory T cells Naïve T cell

Expression CTLA-4 of CTLA-4 Cell-intrinsic: Termination APC APC of response Responding T cell

Cell-extrinsic: APC Treg-mediated Responding T cell suppression of response

24 CTLA-4 competitively inhibits B7-CD28 engagement

APC

B7 CD28

T Cell

Costimulation  T cell activation

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25 CTLA-4 competitively inhibits B7-CD28 engagement

APC APC

B7 B7 CTLA-4 CD28

T Cell T cell (activated T cell or Treg) Costimulation  T cell activation CTLA-4 blocks and removes B7  lack of costimulation  T cell inhibition

26 Consequence of mutations in the CTLA-4 pathway

APC

B7 CD28

T Cell

Unopposed costimulation  Excessive T cell activation

Therapy?

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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)?

28 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)? – 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

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The PD-1 inhibitory pathway

• PD-1 recognizes two widely expressed ligands (PD-L1, PD-L2)

• Knockout of PD-1 leads to (less severe than CTLA-4-KO)

• Role of PD-1 in T cell suppression in chronic , tumors?

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Action of PD-1

Normal response PD-1 engagement

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31 T cell “exhaustion” in chronic viral infections

Memory T cells: Effector enhanced Naïve CD8+ T cells antiviral T cells Acute : responses clearance of Virus Chronic infection: persistence of virus

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+

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T cell activating and inhibitory receptors 33

Inhibitory receptors Activating receptors (costimulators) CTLA-4 CD28 PD-1 ICOS

TIM-3 OX40

TCR T cell

TIGIT GITR

LAG-3 CD137 (4-1BB)

BTLA CD27

34 T cell expansion and contraction (decline)

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

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35 Stages in the life history of lymphocytes

36 Accumulation of memory T cells with age

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37 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

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