Antigen Presentation/Cell cooperation in Antibody

response• Pin Ling ( 凌 斌 ), Ph.D.

ext 5632; lingpin@mail.ncku.edu.tw

• References:

1. Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology (7th ed., 2006), Chapters 7 & 8

QuestionsQuestions

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 .

OutlineOutline•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 cells1. 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 Overview of Dendritic cells in Ag capture & presentationAg 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 Pathogen presentation by MHCsMHCs

Ag Presentation to different T cell

subsets

OutlineOutline•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 Checkpoints in Lymphocyte DevelopmentDevelopment

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, & Down-regulation

T cell Activation by Superantigens

OutlineOutline•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 ( & VpreB). - 5 & VpreB are similar to & 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 => 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

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

OutlineOutline• 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 Germinal center center reactions in T reactions in T cell-mediated cell-mediated Ab responsesAb responsesGerminal centers

(2nd follicle) 1. T-dep B cell

activation2. Somatic hypermutation 3. Isotype switching4. Memory B cells

B-cell development in germinal centers

Cytokines help B-cell isotype Cytokines help B-cell isotype switching & affinity switching & affinity

maturationmaturation

Ig Heavy Ig Heavy chain chain isotype isotype switching-IIswitching-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 Somatic Hypermutation in Ig V regionregion

AID is required in this process.

SUMMARY1. 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.

QuestionQuestion

What happens to the immune system if RAG1 or RAG2 is mutated?