Lymphocyte Activation & Immune Tolerance

• Pin Ling ( 凌 斌 ), Ph.D. ext 5632; lingpin@mail.ncku.edu.tw

• References: 1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 9-11

QuestionQuestion

Severe Combined Immunodeficiency Disease (SCID) Lacking functional T & B cells

What is happened to the immunesystem if RAG1 & RAG2 are mutated?

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 (especially CD4 T cells).

2. Naïve T lymphocytes migrate from Thymus to 2o

Lymphoid organs, whereby encounter Ag presented by APCs (e.g. 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 (e.g. CD28) interact with ligands from APCs.

4. T cell responses decline after Antigen (Crisis) is eliminated.

Activation of Lymphocytes in Lymph Nodes

Phases of T cell Responses

IL-2 – 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 T-cell Receptor Receptor SignalingSignaling

The T-cell The T-cell ImmunologicaImmunological Synapsel Synapse

The interface between

APC cells and T cells: => Prolong

interaction => Enhance

signaling transduction => Determine the

fate of Effector cells

IL-2 Expression during TCR Signaling

Cyclosporin A,FK506

Signal Signal Attenuation by Attenuation by the Inhibitory the Inhibitory Receptor (CTLA-Receptor (CTLA-4)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 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.

Activation of Lymphocytes in Lymph Nodes

The Phases of B cell Responses

Primary vs. Primary vs. Secondary Secondary Ab Ab responsesresponses

B-cell Receptor B-cell Receptor SignalingSignaling

B cell Responses by cross-linking B cell Responses by cross-linking BCRBCR

The Events of T-B cell Interaction

Helper T cell-mediated Helper T cell-mediated B cell activationB cell activation

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 isotype switchingIg Heavy chain isotype switching

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

Ig Heavy chain Ig Heavy chain isotype switchiisotype switching-IIIng-III

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.

Fates of lymphocytes after encounter with antigens

Central vs. Central vs. Peripheral Peripheral ToleranceTolerance

Central T cell ToleranceCentral T cell Tolerance

?

T cell T cell tolerance-A tolerance-A transgenic transgenic mouse modelmouse model

Mechanisms of T cell AnergyMechanisms of T cell Anergy

Regulatory T cell-mediated Regulatory T cell-mediated SuppressionSuppression

Self Ag-induced death Self Ag-induced death of peripheral T cellsof peripheral T cells

Central & Peripheral B cell Central & Peripheral B cell ToleranceTolerance

B cell B cell tolerance -A tolerance -A transgenic transgenic mouse modelmouse model

Features of T cell vs.B cell ToleranceFeatures of T cell vs.B cell 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.

QuestionQuestion

Have you learned something from this series of Immunology Lectures?

Yes More or less Not Sure Definitely Not

CD21/CR2 complement receptor CD21/CR2 complement receptor as as

a Co-receptor for B cellsa Co-receptor for B cells

T-B collaboration & the HaT-B collaboration & the Hapten-Carrier effectpten-Carrier effect