Self Tolerance

Lecture 7

Lymphoid Organs in brief

Primary lymphoid organs

Secondary lymphoid organs Lymph nodes Spleen Mucosal-associated lymph

Can you think of examples?

Lymphoid Organs in brief

High endothelial venule

SLC chemokine

Dendritic cell

Stromal cell

Follicular

1 Trafficking

General Features of

• Discriminate self vs. non-self

• B and T Tregs • Simple: recognition of

• Self-tolerance: still many unknowns

• Multiple Layers of Tolerance

Central Tolerance Immature lymphocytes

Peripheral Tolerance Mature lymphocytes

• Tolerance IS NOT perfect!

T Cell Maturation Pathway

2

• T Cell Central Tolerance - Thymus • In this generative tissue, usually only self are present Foreign antigens are presented in secondary lymphoid sites

• Think back to T cell development: Rearrangement of T cell receptor genes Immature progenitors are resistant Express low level of TCR to Low levels of FAS Double positive - CD4 & CD8 High levels of Bcl-2 (anti-apoptotic)

Double-positive High levels of FAS Very low Bcl-2 Highly sensitive to apoptosis!!!!

Thymic Selection

• Positive Selection T lymphocyte Also called MHC restriction *** Cortical Epithelial Cells Recognition of self MHC MCH + antigen!! T cell receptor diversity

All T cells will have receptors that recognize MHC + antigen Short lived • Negative Selection Thymic dendritic cells general self antigens

Medullary epithelial cells tissue specific antigens

Thymic Selection

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.

HOW CAN THIS WORK?

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

3 T Cell Tolerance - Positive Selection

See video - T Cell development

Negative Selection

Apoptosis Overview

Apoptotic cell being engulfed

4 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

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

5 T Cell Anergy

Regulatory T Cells

UNKNOWN Mechanism

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

Regulatory T Cells

Marker for Tregs FOXp3

Different: have adhesion molecules

6 Tolerance - Mainly Central

Self-Tolerance Summary

7