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Home , Activation, B7 (protein), CD28, CD3 (immunology), CD8, MHC restriction

T Mediated : Selected Features Relevant to

Andrew Lichtman M.D., Ph.D. Dept. of Pathology Brigham and Women’s Hospital Harvard Medical School Lecture Outline

• Overview of functions • T cell recognition/ MHC restriction • Antigen signaling • Costimulation • Effector T cell subsets (Th subsets and CTLs) • that inhibit T cells (CTLA-4, PD-1, others) • Cells that inhibit T cells (Treg) Types of T Cell–Mediated Immune Reactions

CD4+ helper T cells (Th) CD8+ Cytotoxic T (CTL) Microbes that live inside Microbes that live inside Microbes that are readily killed by phagocytes tissue cells Sequence of events in T cell responses

CD4 help for CD8 CD4+ and CD8+ T cells Antigen recognition/ MHC Class Restriction

CD4+ T cell recognition is CD4+ T cells class II MHC (helper T cells) restricted

Peptide from phagocytosed, lysosome- processed (microbial, tumor, normal self) CD8+ T cell CD8+ T cells recognition is (cytotoxic T class I MHC lymphocytes) restricted

Peptide from cytosolic, proteasome-processed protein (microbial, tumor, normal self) Signaling Events in T Cell The signals generated by antigen recognition require the participation of cytoplasmic tails of: • The co-receptor ( CD4 or CD8) • Signaling associated with the TCR (CD3 and zeta)

CD4

TCR T cell DC CD3 Zeta

Relevant to activation of naive T cells ( initiation) and activation of effector T cell TCR signaling: Protein (PTK)-mediated ITAM phosphorylation, recruitment and activation of other

CD3 ζ CD4 Adaptor protein

TCR PI3K

GTP/GDP exchange factor Active Active ZAP-70 PLCγ1 Immunoreceptor tyrosine Inactive γ activation motif PLC 1 Inactive ZAP-70 (ITAM) Downstream signaling; SH2 domain for docking expression; proliferation, PTK domain for further signaling differentiation, effector functions Antigen recognition-Signal 1: Costimulation-Signal 2

• TCR binding to pMHC antigen to MHC is necessary to generate intracellular signals that activate the naïve T cell, ….but is not sufficient. (“Signal 1”) • Additional signals generated by the binding of molecules called costimulators on the APC to costimulatory receptors on the naïve T cell are also necessary for naïve T cell activation. (“costimulatory signals” or “Signal 2”) • Signal 1 without signal 2 leads to anergy, death or Treg differentiation:

Antigen Antigen (Peptide- (Peptide- Naïve CD8 MHC) Naïve CD4 MHC) T cell CD3/ζ T cell CD3/ζ TCR TCR CD8 CD4 DC DC

1 1 2 2

Costimulatory Costimulatory Costimulatory Costimulatory Receptor Receptor Molecule (CD28, CD137) (-1,2; 41BB-L) (CD28) (B7-1,2) Proteins of the B7 and CD28 families: Costimulatory and inhibitory functions

• All are members of Ig superfamily • B7-1, B7-2 and ICOS-L are costimulators • CD28 and ICOS are costimulatory receptors • B7-1 (CD80) and B7-2 (CD86) are the best characterized and probably most important costimulators for naïve T cells . B7-1 and B7-2 are highly homologous, with similar functions. . B7-1 and B7-2 are highly expressed on activated DCs . B7-1 and B7-2 bind to the same receptor on T cells, called CD28 + - + - . CD28 is expressed on most T cells Other T Cell Costimulatory Molecules

TNF/TNFR super family B7/CD28 family Relevance of TCR and costimulatory signaling to immunotherapy

• Chimeric antigen receptors (CARs) make any T cell specific for a

• CARs use TCR complex and costimulatory signaling motifs TCR to activate the T cells complex

Costim Properties of the major subsets of CD4 + helper T cells

DC

(Blocks tumor growth)

IL-4

(Promotes tumor growth) Naïve CD4+ T cell

B cell

Activated CD4+ T cell Differentiation and function of CD8+ T cells

Transcription Cyotkines factors Class I MHC/peptide Blimp-1 Perforin Naïve Granzymes DC CD8+ T cell Tbet IL-2 Eomes IFN-γ IL-12 TNF-α Stat5 CTL Costimulator Costim receptor Stat4 (B7,

Two main functions: CTL 1. Direct killing of target cells 2. Secretion of inflammatory : IFNγ and TNF Putting it all together: CD8+ T cell response to tumor Cell Tumor are injury/death at 1 tumor site will picked up by host generate dendritic cells DAMPs that activate DCs 2 DCs process the antigens and transport to lymph 5 6 nodes

3 4 DCs present tumor Tumor specific peptide antigens to effector T cells naïve T cells, and (CTLs) are generated provide costimulation

(CD4+ T cell responses will14 also occur) CTLA-4 Inhibits T cell Activation: Competitive Blockade of CD28 –B7 Costimulation

Naïve T cell Naïve T cell

1 1 2

DC DC T Cell Activation Costimulation No costimulation

•CTLA-4 binds B7’s with higher affinity than CD28; acts as a competitive inhibitor of CD28 costimulation •CTLA-4 is most effective when B7 expression is low •CTLA4 may also delver inhibitory signals into the T cells it is expressed on PD-1 Inhibits T cell Activation: Inhibitory Signals Block Effector T Cell Activation

Activated CD8+ CTL cell Reduced TCR and CD28 signaling, causing reduced PD-1 TCR production and target cell lysis Peptide-MHC

Infected cell Dead target cell CD28 Inhibited CD8+ CTL B7 PD-1 TCR PD-1 ligand Peptide-MHC (PD-)

No killing PD-1 Inhibits Both TCR and CD28 Signaling

Sharpe A and Pauken K. Nature Rev Immunol 2017 Roles of PD1 in acute , tolerance and cancer

Sharpe A and Pauken K. Nature Rev Immunol 2017 Many T cell inhibitory/regulatory molecules

APC/Tissue cell T cell Regulatory T Cells

CD4 CD25 CTLA-4 Peripheral Treg

Thymic Treg

Cytokines (IL-10, TGF-β) IL-2 sequestration CTLA-4 Others

Costimulation blockade Abbas, Lichtman, Pillai. Cellular and Molecular . Elsevier. 2017