Download Key Concepts in B cell Activation-I

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