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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
QuestionQuestion
What is happened to the immunesystem if RAG1 & RAG2 are mutated?
Severe Combined Immunodeficiency Disease (SCID) Lacking functional T & B cells
OutlineOutline
• Activation of T LymphocytesActivation of T Lymphocytes
•B cell Activation & Ab Production
•Immune Tolerance
•Summary & Question
Key points in T cell activationKey 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 m
olecules (ex. CD28) interact with ligands from APCs.
4. T cell responses decline after the Ag is eliminated.
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
The T-cell The T-cell ImmunologicaImmunological Synapsel Synapse
The interface between
T cells and APC cells => Prolong
interaction => Enhance
signaling transduction
Signal Signal Attenuation by Attenuation by the Inhibitory the Inhibitory Receptor (CTLA-Receptor (CTLA-4)4)
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 c
ells. 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.
OutlineOutline
• Activation of T Lymphocytes
• B cell Activation & Ab ProductiB cell Activation & Ab Productionon
•Immune Tolerance
•Summary & Question
Key points in B cell activation & Key points in B cell activation & Ab productionAb production
1. Overview of B cell activation
2. Signaling Transduction by BCR & its Co-receptor
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-I1. 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 => T- independent (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.
CD21/CR2 complement receptor CD21/CR2 complement receptor as as
a Co-receptor for B cellsa Co-receptor for B cells
Germinal Germinal center center reactions in T reactions in T cell-mediated cell-mediated Ab responsesAb responses
Germinal centers (2nd follicle) 1. T-dep B cell activation2. Somatic hypermutation 3. Isotype switching4. Memory B cells
Ig Heavy chain Ig Heavy chain isotype switchiisotype switching-IIng-II
1. AID (Activation-Induced Deaminase) , ApeI endonuclease & UNG (Uracil N Glycosylase) but not RAG.
2. Other DNA repair proteins
3. Recognize Ig exon or Switch region
Somatic Hypermutation in Ig V regionSomatic Hypermutation in Ig V regionAID is required in this
process.
B cell B cell selection in selection in Germinal Germinal CentersCenters
Only B cells w/ a high affinity for Ag on follicularDCs (FDCs) => Survive
OutlineOutline
• Activation of T Lymphocytes
• B cell Activation & Ab Production
•Immune Tolerance
•Summary & Question
Key Concepts in Immune Tolerance1. 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.
OutlineOutline
• Activation of T Lymphocytes
• B cell Activation & Ab Production
• Immune Tolerance
•Summary &Summary & Question Question
SUMMARY1. T-cell activation requires “Two Signals”: - Primary Signal-TCR/CD3 –Ag/MHC complex - Second Signal (Costimulatory)- Other T cell surface mol
ecules (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.