5. 2018 Adv course. T cell activation. AbbasT Cell Activation, Costimulation and Regulation Abul K. Abbas, MD University of California San Francisco 1 Lecture outline • T cell antigen

2018 Advanced Course in Basic & Clinical Immunology

February 19, 2018

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T Cell Activation, Costimulationand Regulation

Abul K. Abbas, MDUniversity of California San Francisco

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Lecture outline

• T cell antigen recognition and activation

• Costimulation, the B7:CD28 family

• Inhibitory receptors of T cells

• Memory T cells

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Classes of T lymphocytes 3

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

The life history of T lymphocytes4


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Steps in T cell activation

Signals for T cell activation

• Antigen recognition

• Costimulators (second signals)

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

into effector cells

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

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T cell

TCR

APC

MHC/peptide

T cell

Biotin-MHCloaded with

peptideFluorescentstreptavidin

Physiologicantigen recognition

Peptide-MHCtetramer staining

Staining antigen-specific T cells

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


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Molecules involved in T cell activation9

10Formation of the immunological synapse

Regulated way of bringing together key signaling molecules


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• Membrane signal (TCR complex, other receptors) --> biochemical intermediates --> transcription factors

• Calcium -- calcineurin --> NFAT• Ras/MAP-kinase --> AP-1• PKC -- CARMA/BCL-10 --> NFB• PI3-kinase -- Akt --> NFB

• Cytokines --> Jak-Stat

Principal signaling pathways in T cell activation

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)

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

• Costimulators: B7-CD28, others; costimulatory blockade

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The two-signal requirement for lymphocyte 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 B cell complement receptors

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Role of costimulation in T cell activation


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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

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The B7:CD28 families 16


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Major functions of selected CD28:B7 family members

• CD28:B7: initiation of T cell responses

• ICOS:ICOS-L: T cell help in germinal center reactions (antibodyresponses)

• CTLA4:B7: inhibits early T cell responses in lymphoid organs

• PD1:PD-L1,2: inhibits effector T cell responses in peripheral tissues

Act

ivat

ion

Inhibi

tion

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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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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

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

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Inhibitory receptors of the immune system

• 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?

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APCTCR

CD28

NaïveT cell

B7

B7-CD28interaction

B7-CTLA-4interaction

CTLA-4

Proliferation,differentiation

Functional inactivation

The opposing functions of CD28 and CTLA-422

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


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APC

TCR

NaïveT cell

Effector and memory T cells

CD28 B7

APC

CTLA-4

APC

Cell-intrinsic: Termination of response

Responding T cell

Regulatory T cell

APCResponding

T cell

Cell-extrinsic: Treg-mediated suppression of

response

Immune response

Actions of CTLA-4

Expression of CTLA-4

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APC

T Cell

CD28

B7

Costimulation T cell activation

CTLA-4 competitively inhibits B7-CD28 engagement


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APC APC

T Cell

CD28

B7

Costimulation T cell activation

B7 CTLA-4

CTLA-4 blocks and removes B7 lack of costimulation

T cell inhibition

CTLA-4 competitively inhibits B7-CD28 engagement

T cell (activated T cell or Treg)

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APC

T Cell

CD28

B7

Unopposed costimulation Excessive T cell activation

Consequence of mutations in the CTLA-4 pathway

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)?

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 autoimmune disease (less severe than CTLA-4-KO)

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

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Action of PD-1

Normal response PD-1 engagement


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Naïve CD8+ T cells

Effector T cells

Memory T cells:

enhanced antiviral responses

Exhausted T cells: inability to respond to virus

(expression of inhibitory receptors, e.g. PD-1, others)

Virus

Acute infection: clearance of virus

Chronic infection: persistence of virus

T cell “exhaustion” in chronic viral infections

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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 inhibitorof CD28 of CD28 and TCR

Cell type suppressed CD4+ and CD8+ CD8+ > CD4+


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T cell TCR

CD28

ICOS

OX40

GITR

CD137 (4-1BB)

CD27

Activating receptors (costimulators)

Inhibitory receptors

CTLA-4

PD-1

TIM-3

TIGIT

LAG-3

BTLA

T cell activating and inhibitory receptors

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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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Stages in the life history of lymphocytes35

Accumulation of memory T cells with age36


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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

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Documents

5. 2018 Adv course. T cell activation. AbbasT Cell Activation, Costimulation and Regulation Abul K. Abbas, MD University of California San Francisco 1 Lecture outline • T cell antigen