Presentation on theme: "Lecture outline Signals for T cell activation"— Presentation transcript:
1 Lecture outlineSignals for T cell activationCostimulation and the B7:CD28 familyResponses of T cellsCytokines
2 The life history of T lymphocytes Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011cElsevier
3 Principles of lymphocyte activation Lymphocytes are normally in a resting state in lymphoid organs and circulationRapid response to antigen (activation) --> proliferation, change to functionally active effector cells (differentiation)Migration to tissues, where they perform their function of eliminating infectionsMultiple possible steps for therapeutic targeting
5 Recognition of antigen by the TCR The TCR of CD4+ and CD8+T cells recognizes MHC-bound peptide + portions of the MHC.Other T cells (gd T cells, NKT cells) recognize non-peptide antigens; these are small cell populations whose function is unclear.
6 Antigen recognition by T cells Each T cell sees a (self) MHC molecule and a bound peptideDual recognition determines specificity and MHC restrictionMultiple ligands on APCs and receptors on T cells, in addition to the TCR, participate in orchestrating responses to antigensSignaling: clustering of receptors --> activation of kinases (often via “adaptor proteins”) --> activation of transcription factors
7 Receptor-ligand pairs involved in T cell activationDifferent molecules involved in T cell responses toantigen serve distinct functions, seen even in this partial listing.Drugs that block these ligand-receptor pairs have been developedto treat immune-mediated inflammatory diseases, graft rejection.
8 Molecules involved in T cell activation Signal transductionCD4 and CD8 co-receptors recognize MHC molecules (class II or class I) at the same time as the TCR sees the peptide-MHC; CD4 and CD8 provide necessary activating signals for T cellsCD28 is a receptor for “costimulators” expressed on APCs
9 Molecules involved in T cell activation Signal transductionCD4 and CD8 co-receptors recognize MHC molecules (class II or class I) at the same time as the TCR sees the peptide-MHC; CD4 and CD8 provide necessary activating signals for T cellsCD28 is a receptor for “costimulators” expressed on APCsStrengthen adhesion with antigen-presenting cellsIntegrins function as adhesion moleculesAffinity of integrins is increased by chemokines produced during inflammation, and by antigen recognition by TCRsControl routes of T cell migrationSelectins and integrins control migration of naïve T cells through lymph nodes and of effector and memory T cells to sites of infectionTherapeutic targets
10 Formation of the immunological synapse Signaling molecules orient to one region of the cell within seconds of antigen recognition
11 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 MAb’s to block leukocyte migration into tissues“Costimulators”: CD28, others; costimulatory blockade
12 The two-signal requirement for lymphocyte activation Costimulation: signal(s)in addition to antigen that are needed to initiate adaptive immuneresponsesBest defined for CD4+ TcellsMultiple pairs of ligandson APCs and receptorson T cells may serve thisfunction; best definedare the B7-CD28 families of proteinsAbbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011cElsevier
13 Two signal requirement for T cell activation Naïve lymphocytes need two signals to initiate their responsesSignal 1: antigen recognitionEnsures that the response is antigen-specificSignal 2: costimulators induced on APCs during infection (or upon recognition of necrotic cells)Ensures that the immune system responds best to microbes (or dangerous insults, such as tumors) and not to harmless antigensAdjuvants stimulate expression of costimulators
15 The B7: CD28 family Different members of the B7-CD28 families serve different roles instimulating and suppressingimmune responses.
16 Major functions of selected B7-CD28 family members B7-CD28: initiation of immune responsesICOS-ICOS-L: role in B cell activation in germinal centersB7-CTLA-4: inhibits early T cell responses in lymphoid organsPD-1:PD-L1,2: inhibits effector T cell responses in peripheral tissues
17 The opposing functions of CD28 and CTLA-4 B7CD28APCB7-CD28interactionNaïveT cellTCRProliferation,differentiationCTLA-4B7-CTLA-4interactionFunctionalinactivationInhibitory pathways function normally to preventresponses to self antigens: demonstrated by thefinding that blocking or eliminating these inhibitors(CTLA-4, PD-1) causes autoimmune disease
18 Blocking CTLA-4 promotes tumor rejection Tumor recognition by T cells leads to engagement of CTLA-4 on the T cells and inhibition of immune responses. Blocking CTLA-4 increases anti-tumor response and leads to tumor rejection.
19 Inhibitory role of PD-1 in a chronic infection Virus-specificT cell responseResidual virusIn a chronic viral infection in mice, recognition of virus by specific T cells leads to PD-1 engagement, inhibition of T cell responses, and persistence of the virus. Blocking the PD-1 pathway releases the inhibition, enhances the T cell response, and leads to viral clearance.
20 Inhibitory receptors Prevent reactions against self antigens Mediate immunosuppression in chronic infections (HCV, HIV)Limit responses to tumorsSimilar roles are established for both CTLA-4 and PD-1
21 The balance between activation and inhibition How does a T cell choose to use CD28 to be activated or CTLA-4 to shut down?
22 The balance between activation and inhibition How does a T cell choose to use CD28 to be activated or CTLA-4 to shut down?Low B7 (e.g. when DC is displaying self antigen) --> engagement of high-affinity CTLA-4High B7 (e.g. after microbe encounter) --> engagement of lower affinity CD28Not well understood for the PD-1 pathway
23 Therapeutics based on the B7:CD28/CTLA-4 family 1. Costimulatory blockadeCTLA-4.Ig is used for diseases caused by ….?
24 Therapeutics based on the B7:CD28/CTLA-4 family 1. Costimulatory blockadeCTLA-4.Ig is used for diseases caused by excessiveT cell activation -- rheumatoid arthritis, graft rejection; not yet approved for IBD, psoriasis
25 Therapeutics based on the B7:CD28/CTLA-4 family 2. Inhibiting the inhibitorAnti-CTLA-4 antibody is used for ….?
26 Therapeutics based on the B7:CD28/CTLA-4 family 2. Inhibiting the inhibitorAnti-CTLA-4 antibody is approved for tumorimmunotherapy (enhancing immune responses against tumors)Even more impressive early clinical trial results with anti-PD-1 in cancer patients
27 Costimulation Required for initiating T cell responses Many proteins on APCs and their receptors on T cells shown to “costimulate” (function with antigen to activate T cells); most important costimulators are B7:CD28Ensures that T cells respond to microbes (the inducers of costimulators) and not to harmless antigensSource of costimulation in responses to tumors and transplants: products of dead cells?Therapeutic targets
28 T cell expansion and contraction (decline) 102104106714200Days after infection# of microbe-specific T cellsCD8 cellsCD4 cellsInfectionClonalexpansionContraction(homeostasis)MemoryMany aspects of T cell responses and functions are mediatedby cytokines: initial activation -- IL-2; maintenance of memory cells -- IL-7; effector functions -- various
29 CytokinesSecreted proteins that mediate immune and inflammatory reactions, and communications among leukocytes and other cellsProduced transiently in response to extrinsic stimuliBind to high-affinity receptors on target cellsActions are most often autocrine and paracrine, rarely endocrineCytokines are pleiotropic (one cytokine has multiple actions) and redundant (different cytokines have similar actions)
30 Role of IL-2 and IL-2 receptors in T cell proliferation Production of IL-2 and expression of high-affinity IL-2 receptorsare both dependent on antigen recognition + costimulation
31 Clonal expansion (proliferation) of T cells Stimulated mainly by autocrine IL-2T cell stimulation by antigen + costimulators induces secretion of IL-2 and expression of high-affinity IL-2 receptorsTherefore, antigen-stimulated T cells are the ones that expand preferentially in any immune response, keeping pace with replicating microbes
32 Clonal expansion (proliferation) of T cells Stimulated mainly by autocrine IL-2T cell stimulation by antigen + costimulators induces secretion of IL-2 and expression of high-affinity IL-2 receptorsTherefore, antigen-stimulated T cells are the ones that expand preferentially in any immune response, keeping pace with replicating microbesCD8+ T cells may expand >50,000-fold within a week after an acute viral infection with 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
33 Naïve T cells differentiate into functional effector cells Effector T cellsCD4+ helperT cellsShow naïve CD8 also?Cytokinesecretion+ antigenDifferentiation+ antigenAPCNaïve T cell:Can recognize antigen but incapable of any functionsCellkillingCD8+ CTLs
34 Memory T cells Long-lived, functionally silent More numerous than naïve cells specific for the antigen; respond more rapidly than do naïve cells -- explains why secondary response is “better” than primary responseDevelop from antigen-stimulated T cellsMay consist of multiple subsetsSome migrate to lymphoid organs (like naïve T cells), and proliferate and differentiate rapidly in response to antigen challenge (repeat infection)Others migrate to peripheral sites of infection, and rapidly perform effector functions upon encountering the antigen
35 The life history of T lymphocytes Precursors mature in the thymusNaïve CD4+ and CD8+ T cells enter the circulationNaïve T cells circulate through lymph nodesand find antigensClonal expansion;differentiation into effector and memory cellsEffector T cells migrate to sites of infectionEradication of infection