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Lecture 34

MIMM 214 Lecture 34: Lymphocyte Development, Negative Regulation, and Immune Tolerance IV
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Department
Microbiology and Immun (Sci)
Course
MIMM 214
Professor
Claire Trottier
Semester
Winter

Description
Lecture 34 Friday, March 31, 2017 From last lecture (cont'd) 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-peptide:MHC complexes are deleted (die of 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-peptide:MHC complexes Key anatomy and cell types • Cortical epithelial cells o Responsible for +ve selection o Not radio-sensitive • Medullary epithelial cells o Responsible for -ve selection o Originate from BM precursors o Are radio-sensitive • Macrophages o There to phagocytose apoptotic cells Question • What is their MHC restriction? o MHC A only - cortical medullary cells (radio-resistant) are responsible for inducing MHC restriction Recall • MHC restriction is to the MHC of the CORTICAL epithelial cells (radio-resistant cells) o These cells mediate most positive selection • Tolerance is to the MHC is the MEDULLARY bone marrow-derived cells (radio-sensitive cells) o These cells mediate most negative selection How do we assess MHC restriction? • X, y = the MHC type being tested How do we assess tolerance? • Skin graft experiments What is the MHC restriction? Peripheral tolerance • Peripheral mechanisms of tolerance also protect against autoreactive thymocytes o Important for self-reactive T cells that escape negative selection in thymus o Strong self-antigen signaling through the TCR in the absence of costimulation may drive the T cells into anergy (nonresponsiveness) B CELL DEVELOPMENT AND 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 give rise to an Ig that shows self-tolerance • Negative selection (deletion) of autoreactive B cells Negative selection of B cells in BM • BCRs are tested against self-antigens - three possible outcomes o Clonal deletion of strongly autoreactive cells • Through apoptosis • Termed central tolerance as it occurs in bone marrow o Receptor editing - reactivation of recombination machinery o Anergy - induction of nonresponsiveness to further stimuli (even self-antigen stimuli) • There is no known AIRE equivalent - range of self Ag available is lower • Receptor editing of potentially autoreactive receptors occurs in light chains o A function antibody may bind to self antigens o Recombination machinery can be turned back on • This method is a "last-ditch effort" to salvage the rearrangement (or at least inactivate it) Question • There is a smaller range of self antigens available during negative selection for B cells compared to T cells • What might a consequence of this, and what additional mechanism helps prevent autoreactive B cells from becoming activated? o A consequence of this could be that autoreactive B cells may
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