Lecture 11-Lymphocyte development II

Lecture - Dueling repressors Runx3 and Thpok at the heart of the CD4/CD8 lineage choice Lie Wang Rmy Bosselut Journal of Immunology 2009 183

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1 “Dueling repressors” Runx3 and Thpok at the heart of the CD4/CD8 lineage choice Lie Wang, Rémy Bosselut. Journal of Immunology, 2009, 183: 2903–2910 Possible basis for TCR signal strength input to bias CD4/CD8 lineage decision network Rothenberg, 2009 Immunol. Cell Biol. 87(2):109-12. Positive and negative selection: problems faced by T and B cells • Both T and B cells generate receptors with random specificities • Both run the risk of autoreactive receptors in repertoire • Positive feedback inherent in immune responses could create overwhelming autoimmunity • Initial repertoire purging… nice idea, but how? Problems of repertoire selection, continued TCR and Ig repertoires are selected before cells go to periphery Random nature of VDJ rearrangement + allelic exclusion means lots of cells with failed or autoreactive receptors Selection needed in favor of cells with some receptor (no receptor death) Selection needed to remove many/most cells with highly self-reactive receptors
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2 Positive vs. negative selection: what is the choice that the cells have to make? T cell case is easier to study because +, - selection occur in different thymic domains Signal strength distinguishing positive from negative selection Building an assay system for TCR-ag recognition in development: Positive selection of CD8 + cells in OT-1 TCR-tg thymus is blocked by lack of surface MHC cl. I Hogquist et al. 1994 b 2m is common, soluble chain required for membrane stabilization of all MHC cl. I structures… single-gene knockout blocks almost all cl. I MHC surface expression Optimal OT-1 target antigen peptide addback causes deletion in fetal thymus organ culture, though potency is less without b 2 m Hogquist et al. 1994
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3 Variants of antigenic peptide mediate positive selection in FTOC Hogquist et al. 1994 Hierarchy of strength for positive selection: a different hierarchy than for effector recognition Positive selection is mostly by peptide-MHC complexes that are weak interactors with TCR
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This note was uploaded on 01/03/2012 for the course BI 144 taught by Professor List during the Fall '10 term at Caltech.

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Lecture - Dueling repressors Runx3 and Thpok at the heart of the CD4/CD8 lineage choice Lie Wang Rmy Bosselut Journal of Immunology 2009 183

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