Transcript il2
T Cell Activation What is activation? increased transcription, translation cell cycle entry, proliferation increased ‘help’ for B cells (CD40L, cytokines) + CTL (cytokines) increased cell-mediated effector function (granzyme; FasL) How are T cells activated in vivo? Concept of co-stimulation Co-stimulatory molecules, signaling pathways Negative regulation of T cell activation Overview of TCR/CD3 Signaling Pathways 1 3 2 IP3 AP-1 Transcription Factors NF-kB Global changes in transcription upon T cell activation Gene Induction after Ag recognition Gene Induction after Ag recognition Gene Induction after Ag recognition T cell trafficking and activation by APC’s Dendritic cells sample antigens in peripheral tissues, mature and migrate to lymph nodes T Cell Circulation Selectin Proteins Help Direct T Cell Traffic in vivo Naive T Cells Integrins also help direct T cell traffic and coordinate binding to different cell types Accessory and Co-Stimulatory Molecules in T Cell Activation Strength (Affinity) of Various Receptor/Ligand Systems Accessory Molecules Help Stabilize T Cell/APC Interactions ‘Immunological synapse’ ‘Supra-molecular activation cluster (SMAC)’ “Inside-out” signaling upregulates T cell adhesion to APC APC Phenotypes “Two-signal” model of lymphocyte activation Burnet - clonal selection hypothesis - B cells (1950s) Bretscher and Cohn (1970) what about hypermutation? ‘helper’ cell (overlapping Ag specif.) for B cell responses Lafferty and Cunningham (1975) self-reactive cells must be removed during development second signal for helper cell (from APC) Janeway and Medzhitov (~1989-1992) activation signal for APC (pattern-recog. receptor) PRR’s bind to conserved structures on pathogens Roles for Co-Stimulation in T Cell Responses Increases efficiency of T cell activation increases signaling proliferation, cytokine production effects both quantitative + qualitative Increases T cell survival Helps ensure activation by appropriate cells i.e. by cells w/ligands for costim. molecules professional APC particularly important for naive cells Co-stimulation + T cell activation B Cell activation through surface Ig is aided by a co-receptor complex Molecules with T cell co-stimulatory activity Mucin domain TIM-1 (upregulated) TIM-4 Yes Yes ? ? No CD28 44 kD surface glycoprotein Cloned in Brian Seed’s lab (1984) Later shown to augment T cell proliferation Also shown to increase IL-2 production Shown by Allison and colleagues and Jenkins and Schwartz to prevent anergy in T cell clones stimulated through TCR alone Cytoplasmic domain required (signaling) T Cell Clone Experiments Demonstrating the Importance of Co-stimulation Note: No IL-2 produced Co-stimulation Can Be Provided In Trans Fixed APC + untreated APC Fixed APC + anti-CD28 Ab Function of IL-2 in T Cell Priming/Expansion IL-2 is a critical growth factor for expansion of effector T cells and is a target of co-stimulation Generation of Effector CTL w/T Cell Help CD28 Signaling CD28 cytoplasmic domain CD28 - downstream signaling Some MAPK pathways are targets for co-stimulatory signals CD28 NF-kB activation by TCR and CD28 CD28 PI-3K CARMA1 Akt Contribution of CD28 to NFAT Activation Negative Regulation of T Cell Activation CD28 and CTLA-4 After a T cell becomes activated, it up-regulates expression of CTLA-4 on the cell surface. CTLA-4 binds B7 with about 10x higher affinity than does CD28 This appears to act as a damper on activation Regulation of CTLA-4 Expression Lack of CTLA-4 Disrupts Normal T Cell Homeostasis wild-type knockout This suggests that there is probably some low-level ‘activation’ happening all the time in vivo, which CTLA-4 normally dampens 1 cm Lymphadenopathy CTLA4-Ig Suppresses Immune Responses CTLA4-Ig in the clinic: -transplants -autoimmune diseases Also evidence that CTLA4-Ig binding to B7 on APC can result in production of an inhibitory factor (IDO). CD28 and B7 Family Members Speculative model for PD-1 Function Summary T cell activation is aided by accessory receptors Activation results in global changes in gene expression Co-stimulatory molecules are important for activation and function of T cells Related inhibitory molecules play a role in limiting immune responses