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Lecture 34

MIMM 214 Lecture 34: Lymphocyte Development, Negative Regulation, and Immune Tolerance IV

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Microbiology and Immun (Sci)
MIMM 214
Claire Trottier

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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