Transcript B-cell activation

Antigen Presentation/Cell
cooperation in Antibody response
• Pin Ling (凌 斌), Ph.D.
ext 5632; [email protected]
• References:
1. Male D., J. Brostoff, D. B Roth, and I.
Roitt Immunology (7th ed., 2006),
Chapters 7 & 8
Questions
What is the advantage of MHC
Polymorphism? Is that good if MHC is as
diverse as Ig or TCR?
 MHC polymorphism may provide a broader protective
immunity in a population during pathogen infection .
Outline
• Antigen presentation to T cells
• T-cell activation
• Cell cooperation in Ab response (B-cell
activation)
• B cell affinity maturation
• Summary & Question
Key Concepts in Ag presentation
between APCs & T cells
1. Most T cells recognize only peptides, whereas B cells can
recognize peptides, lipids, nucleic acids,….etc.
NK-T cells can recognize lipids.
2. T cells only recognize peptides displayed by MHC molecules
on Ag-presenting cells (APCs).
3. APCs are responsible for capturing and displaying different
Ags to T cells.
4. APCs serve two key functions for T cell activation:
1st function => process protein Ags to small peptides
=> form & present the peptide-MHC complex to
T cells
2nd function => provide 2nd co-stimulatory signals, e.g.
Cytokines & Surface Molecules
T cells require APCs to respond to
a specific Ag
Features of different APCs
Localization of APCs in lymph
nodes
Functions of different APCs
Overview of Dendritic cells in Ag
capture & presentation
The Class I MHC pathway for Ag
(intracellular) Presentation
The Class II MHC pathway of Ag
(extracellular) Presentation
Cross presentation of
exogenous peptides by
MHC-I on DCs
Pathogen presentation by MHCs
Ag Presentation to different T cell
subsets
Outline
• Antigen presentation to T cells
• T-cell activation
• Cell cooperation in Ab response (B-cell
activation)
• B cell affinity maturation
• Summary & Question
Key Concepts in lymphocyte development
1. Lymphocyte development-A process of differentiation
of lymphoid progenitor cells into mature lymphocytes
(T & B).
2. Rearrangement and expression of Ag receptor genes
are associated with lymphocyte development.
3. Selection events are involved in preserving cells w/
correct Ag receptors and eliminating dangerous cells
w/ self-recognition Ag receptor.
4. Proliferation in the early lymphocyte development is
stimulated by IL-7.
Checkpoints in Lymphocyte Development
Stages of T lymphocyte development-I
Maturation of T lymphocytes in Thymus
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 (e. g. CD28) interact with ligands from APCs.
4. T cell responses decline after Ag is eliminated.
Key Concepts in T cell Activation-II
5. 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
6. Differentiation of naïve CD8 T cells requires Signals:
- Ag presentation, Cytokines (eg. IL-12), and Effector
CD4 T cells in some cases.
7. The Best characterized costimulatory pathway:
CD28 (T cell)-B7 (APC) interaction.
Key Molecules in APC-T cell
Interaction (Immunological Synapse)
T-cell Activation
Signaling
T-cell Activation,
Anergy, & Downregulation
T cell Activation by Superantigens
Outline
• Antigen presentation to T cells
• T-cell activation
• Cell cooperation in Ab response (B-cell
activation)
• B cell affinity maturation
• Summary & Question
Features of B lymphocyte development
1. Maturation of B Lymphocytes development
- Rearrangement & expression of Ig gene in a precise order
- Selection & proliferation of pre-B cells via pre-Ag receptor
2. Selection of the mature B cell repertoire
- Self Ag => Affect the strength of the BCR signal
- Immature B cells => self Ag/high avidity => Receptor editing =>
Additional L chain recombination => Not Self-reactive
Fail to receptor editing => Apoptosis
3. During this maturation, B cell lineage cells go through
distinct stages => A specific Ig gene expression
=> Distinct surface markers
4. At Pre-B cell stage, H chain recombination occurs first and
associates w/ Surrogate light chains (l5 & VpreB).
- l5 & VpreB are similar to k & l light chains but invariant
- form pre-B cell receptor => Development
Stages of B lymphocyte development-I
Stages of B lymphocyte development
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
The Phases of B cell Responses
Cell cooperation
in B cell Responses
1. APCs w/Ag  T
cells
2. B cell w/Ag  Th
cells
3. B cells activation
=> Plasma cells
=> memory
B-cell Activation Signaling
Interface between T and B-cells
Outline
• Antigen presentation to T cells
• T-cell activation
• Cell cooperation in Ab response (B-cell
activation)
• B cell affinity maturation (in Germinal
Center)
• Summary & Question
Key Concepts in B cell Activation-II
6. Features of antibody responses in vivo include:
•
the enhanced secondary response;
•
isotype switching;
•
affinity maturation;
•
the development of memory.
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
B-cell development in germinal
centers
Cytokines help B-cell isotype
switching & affinity maturation
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
Somatic Hypermutation in Ig V region
AID is required in this process.
SUMMARY
1. Two classes of MHC molecules.
- Class-I MHC => peptides from cytosolic (intracellular)
proteins => CD8 T cells
- Class-II MHC => peptides from extracellular (exogenous)
proteins from phagocytosis => CD4 T cells
2. APCs serve two key functions for T cell activation:
1st function => process & present Ag peptides w/MHC to
T cells
2nd function => provide 2nd co-stimulatory signals, ex.
cytokines & surface molecules
3. B cell activation mediates “Humoral Immune Responses”.
Isotype switching & Hypermutation are key features
in T cell-dep humoral immune responses.
Question
What happens to the immune system
if RAG1 or RAG2 is mutated?