Self Tolerance
Lecture 7
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
SLC chemokine
Dendritic cell
Stromal cell
Follicular Dendritic cell
1 Lymphocyte Trafficking
General Features of Immune Tolerance
• Discriminate self vs. non-self
• B and T lymphocytes Tregs • Simple: recognition of antigen
• 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
• T Cell Central Tolerance - Thymus • In this generative tissue, usually only self antigens 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 apoptosis 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 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
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 B Cell Tolerance - Mainly Central
Self-Tolerance Summary
7