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1
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
7
B Cell Tolerance - Mainly Central
Self-Tolerance Summary
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