MIMM 214 Lecture Notes - Lecture 33: Thymectomy, Linkage Disequilibrium, Immunoglobulin Light Chain
7 Jun 2018
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Lecture 34 – March 31, 2017
Negative selection of thymocytes is mediated mostly by radio-sensitive bone marrow-derived cells
- Negative selection ensures self-tolerance
- Thymocytes whose TCR shows too much reactivity for self p:MHC complexes are deleted
(apoptosis)
- AIRE is a protein that ensures expression of many tissue specific proteins in the thymus
o Source of peptides on which to test tolerance to self p:MHC complexes
Key anatomy and cell types
- Cortical epithelial cells
o Responsible for positive selection
o Not radio sensitive
- Medullary epithelial cells
o Negative selection
o Originate from bone marrow precursors
o Radio sensitive
- Macrophages
o Phagocytose apoptotic cells
Question
- Answer: Antigen is restricted to MHC A (cortical epithelial cells are resistant to radiation)
Recall
- MHC restriction is to the MHC of the cortical epithelial cells
o Mediate positive selction
- Tolerance is to the MHC of the medullary bone marrow derived cells
o Negative selection
How do we assess MHC restriction
- Mouse T cells + Ag
o MHC x APC → response = MHC restriction
How do we assess tolerance
- Skin
- Skin survival or rejection will show if tolerant
What is MHC restriction?
- Even if not restricted to a certain MHC, there might still be response because of allorecognition
Peripheral tolerance
- Peripheral mechanisms of tolerance also protect against autoreactive thymocytes
o Important for self-reactive T cells that escape negative selection in thymus
find more resources at oneclass.com
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o Strong self-antigen signaling through the TCR in the absence of costimulation may drive
the T cells into anergy (nonresponsivness)
- Recall clonal anergy
o In the absence of costimulation, T cells become anergic
o If no costimulation
o Can no longer respond to stimulation
B cell development & Tolerance
- B cell development begins in the bone marrow and is completed in periphery (including spleen)
- Only negative selection required
- No need for MHC restriction
- B cell development occurs in the bone marrow
- Needs to ensure
o Proper gene rearrangement of H and L chain genes to gie rise to an Ig that shos…
o Self-tolerance = negative selection (deletion) of autoreactive B cells
Outcomes
Negative selection of B cells in the bone marrow
- Tested against self antigens
- Three outcomes
o Clonal deletion or strongly autoreactive
▪ Through apoptosis
▪ Termed central tolerance as it occurs in the bone marrow
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Negative selection of thymocytes is mediated mostly by radio-sensitive bone marrow-derived cells. Thymocytes whose tcr shows too much reactivity for self p:mhc complexes are deleted (apoptosis) Aire is a protein that ensures expression of many tissue specific proteins in the thymus: source of peptides on which to test tolerance to self p:mhc complexes. Cortical epithelial cells: responsible for positive selection, not radio sensitive. Medullary epithelial cells: negative selection, originate from bone marrow precursors, radio sensitive. Answer: antigen is restricted to mhc a (cortical epithelial cells are resistant to radiation) Mhc restriction is to the mhc of the cortical epithelial cells: mediate positive selction. Tolerance is to the mhc of the medullary bone marrow derived cells: negative selection. Mouse t cells + ag: mhc x apc response = mhc restriction. Skin survival or rejection will show if tolerant. Even if not restricted to a certain mhc, there might still be response because of allorecognition.
