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Lecture 7

Self Tolerance

Lymphoid Organs in brief

Primary lymphoid organs Bone marrow Thymus

Secondary lymphoid organs Lymph nodes Spleen Mucosal-associated lymph

Can you think of examples?

Lymphoid Organs in brief

High endothelial venule

Stromal cell

Dendritic cell

SLC chemokine

Follicular Dendritic cell

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Lymphocyte Trafficking

General Features of Immune Tolerance

• Multiple Layers of Tolerance

Central Tolerance

• Discriminate self vs. non-self

Immature lymphocytes

Peripheral Tolerance Mature lymphocytes

• Self-tolerance: still many unknowns

• Simple: recognition of antigen Tregs

• B and T lymphocytes

• Tolerance IS NOT perfect!

T Cell Maturation Pathway

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T Cell Central Tolerance

• T Cell Central Tolerance - Thymus

Foreign antigens are presented in secondary lymphoid sites

• Think back to T cell development:

• In this generative tissue, usually only self antigens are present

Rearrangement of T cell receptor genes

Express low level of TCR Immature progenitors are resistant

to apoptosis Low levels of FAS

High levels of Bcl-2 (anti-apoptotic) Double positive - CD4 & CD8

Double-positive High levels of FAS

Very low Bcl-2 Highly sensitive to

apoptosis!!!!

Thymic Selection

T lymphocyte ***

• Positive Selection

• Negative Selection

Cortical Epithelial Cells

Recognition of self MHC

Also called MHC restriction

MCH + antigen!!

T cell receptor diversity

All T cells will have receptors that recognize MHC + antigen

Thymic dendritic cells general self antigens

Short lived

Medullary epithelial cells tissue specific antigens

Thymic Selection

HOW CAN THIS WORK?

1. TCRs must recognize MHC+self antigen to pass through positive selection. 2. TCRs must mediate negative selection - ie. Self tolerance. 3. Later, must also signal activation when faced with foreign peptides.

1. Positive selection Relatively weak TCR/MCH+self antigen 2. Negative selection Strong TCR/ MCH+ self antigen 3. T cell activation Strong TCR / MCH + antigen from APC

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T Cell Tolerance - Positive Selection

See video - T Cell development

Negative Selection

Apoptosis Overview

Apoptotic cell being engulfed

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Two Distinct T Cell Pathways

Programmed Cell Death

Two distinct Pathways

Signaling & activation of Caspases

Intrinsic major pathway in all cells regulation of mito integrity release of key apoptotic factors Cytochrome C

Extrinsic death receptors (Fas) trimeric cell surface proteins bind to specific ligands (FasL) pro-apoptotic - mito leakage

T Cell Peripheral Tolerance

Layering of Tolerance Induction

1. Central tolerance - thymus**

2. Traffic patterns

3. Secondary Lymph organs

4. Missing signal

5. Activation

Peripheral Tolerance

T cell receptors that recognize rare thymus antigens

Too rare to have sufficient MCH/peptide complexes

Functional Ignorance

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T Cell Anergy

Regulatory T Cells

Occurs in the thymus as well - subset of CD4 cells Bypass negative selective and mature into Tregs

This means that they have high affinity for self antigens

UNKNOWN Mechanism

Regulatory T Cells

Marker for Tregs FOXp3

Different: have adhesion molecules

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B Cell Tolerance - Mainly Central

Self-Tolerance Summary