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Lymphocyte Activation & Immune Tolerance • Pin Ling (凌 斌), Ph.D. ext 5632; [email protected] • References: 1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 9-11 Question What is happened to the immune system if RAG1 & RAG2 are mutated? Severe Combined Immunodeficiency Disease (SCID) Lacking functional T & B cells Outline • Activation of T Lymphocytes • B cell Activation & Ab Production • Immune Tolerance • Summary & Question Key points in T cell activation 1. Activation of CD4 & CD8 T cells 2. Role of Costimulators in T cell activation 3. Signaling Transduction by the TCR/CD3 complex 4. T cell signal “Attenuation”: Roles of inhibitory receptors & Protein degradation Key Concepts in T cell Activation-I 1. Adaptive immune responses are initiated and mediated by T-cell activation. 2. Naïve T lymphocytes migrate from Thymus to 2o Lymphoid organs, whereby encounter Ag presented by APCs (eg. DCs) and then become activated. 3. T-cell activation requires Two Signals: - Primary Signal-TCR/CD3 –Ag/MHC complex - Second Signal (Costimulatory)- Other T cell surface molecules (ex. CD28) interact with ligands from APCs. 4. T cell responses decline after the Ag is eliminated. Activation of Lymphocytes in Lymph Nodes Phases of T cell Responses IL2 –A T cell autocrine factor Cross presentation (priming) of Ag to CD8 T cells DC has an unique feature: Allow protein traffic from endosomal vesicles to the cytosol Ag-MHC-I presentation Ingest virus-infected or tumor cells => CD8 T cells Role of CD4 T helper cells in the differentiation of CD8 T cells Functions of co-stimulation in T cell activation T-cell Receptor Signaling The T-cell Immunological Synapse The interface between T cells and APC cells => Prolong interaction => Enhance signaling transduction IL-2 Expression during TCR Signaling Cyclosporin A Signal Attenuation by the Inhibitory Receptor (CTLA-4) TCR Signal Termination by Protein Degradation Key Concepts in T cell Activation-II 1. Activated CD4 T helper type -1 (Th1) cells regulate the cell-mediated immunity (CMI) => Macrophages & CD8 T cells. Th2 cells help Humoral immunity => B cell activation 2. Differentiation of naïve CD8 T cells requires Signals: - Ag presentation, Cytokines (eg. IL-12), and Effector CD4 T cells in some cases. 3. The Best characterized costimulatory pathway: CD28 (T cell)-B7 (APC) interaction. Outline • Activation of T Lymphocytes • B cell Activation & Ab Production • Immune Tolerance • Summary & Question Key points in B cell activation & Ab production 1. Overview of B cell activation 2. Signaling Transduction by BCR & its Coreceptor 3. Mechanisms of CD4 T helper cell-mediated B cell activation 4. The Germinal Center Reaction: -Isotype switching -Affinity maturation (Somatic Hypermutation) Key Concepts in B cell Activation-I 1. B cell activation mediates Humoral Immune Responses. 2. Activating B cells => Ab responses => protein Ag => Require CD4 T helper cells => These protein Ag => T-dependent (TD) Ag 3. Activating B cells => Ab responses to multivalent Ags w/ repeating epitopes (lipids, polysaccharides) => No CD4 T helper cells => These lipid & polysaccharide Ags => Tindependent (TI) Ag 4. Heavy chain isotype switching & Hypermutation are often seen in T cell-dependent humoral immune responses. 5. Primary & 2nd Ab responses differ qualitatively & quantitatively. Activation of Lymphocytes in Lymph Nodes Phases of B cell Responses Primary vs. Secondary Ab responses B-cell Receptor Signaling CD21/CR2 complement receptor as a Co-receptor for B cells B cell Responses by cross-linking BCR Events of T-B cell Interaction T-B collaboration & the Hapten-Carrier effect Helper T cell-mediated B cell activation Germinal center reactions in T cell-mediated Ab responses Germinal centers (2nd follicle) 1. T-dep B cell activation 2. Somatic hypermutation 3. Isotype switching 4. Memory B cells Ig Heavy chain isotype switching Ig Heavy chain isotype switching-II 1. AID (ActivationInduced Deaminase) , ApeI endonuclease & UNG (Uracil N Glycosylase) but not RAG. 2. Other DNA repair proteins 3. Recognize Ig exon or Switch region Ig Heavy chain isotype switching-III Somatic Hypermutation in Ig V region AID is required in this process. B cell selection in Germinal Centers Only B cells w/ a high affinity for Ag on follicular DCs (FDCs) => Survive Outline • Activation of T Lymphocytes • B cell Activation & Ab Production • Immune Tolerance • Summary & Question Key Concepts in Immune Tolerance 1. Self-tolerance may be induced in immature self-reactive lymphocytes in primary lymphoid organs (Central tolerance) or mature lymphocytes in peripheral sites (Peripheral tolerance). 2. Central Tolerance => Cell Death (T & B cells) (Negative selection) => Receptor Editing (B cells) => A change in functional abilities (Regulatory T cells) 3. Peripheral Tolerance Mature lymphocytes self Ags => No response (Anergy) => Cell Death 4. Foreign Ags may be administered in ways that inhibit immune responses by inducing tolerance. Fates of lymphocytes after encounter with antigens Central vs. Peripheral Tolerance Central T cell Tolerance ? T cell tolerance-A transgenic mouse model Mechanisms of T cell Anergy Regulatory T cell-mediated Suppression Self Ag-induced death of peripheral T cells Central & Peripheral B cell Tolerance Features of T cell vs.B cell Tolerance Outline • Activation of T Lymphocytes • B cell Activation & Ab Production • Immune Tolerance • Summary & Question SUMMARY 1. T-cell activation requires “Two Signals”: - Primary Signal-TCR/CD3 –Ag/MHC complex - Second Signal (Costimulatory)- Other T cell surface molecules (eg. CD28) interact with ligands from APCs. 2. B cell activation mediates “Humoral Immune Responses”. Isotype switching & Hypermutation are key features in T cell-dep humoral immune responses. 3. Self-tolerance may be induced in immature self-reactive lymphocytes in primary lymphoid organs (Central tolerance) or mature lymphocytes in peripheral sites (Peripheral tolerance). 4. The failure of self tolerance leads to autoimmune diseases. Question Have you learned something from this series of Immunology Lectures? Yes More or less Not Sure Definitely Not