1“Dueling repressors” Runx3 and Thpok at the heart of the CD4/CD8 lineage choiceLie Wang, Rémy Bosselut. Journal of Immunology, 2009, 183: 2903–2910Possible basis for TCR signal strength input to bias CD4/CD8 lineage decision networkRothenberg, 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 somereceptor (no receptor death)•Selection needed to remove many/most cells with highly self-reactive receptors
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2Positive 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 thymicdomainsSignal strength distinguishing positive from negative selectionBuilding 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. IHogquist et al. 1994b2m is common, soluble chain required for membrane stabilization of all MHC cl. I structures… single-gene knockout blocks almost all cl. I MHC surface expressionOptimal OT-1 target antigen peptide addback causes deletion in fetal thymus organ culture, though potency is less without b2mHogquist et al. 1994