Failure of HY-Specific Thymocytes to Escape Negative Selection by Receptor Editing

Abstract

Editing of autoreactive antigen receptors by secondary V(D)J recombination efficiently rescues B lymphocyte precursors from apoptosis induced by negative selection, but its role has not been rigorously assessed in T cell development. We therefore generated a transgenic mouse model in which self-reactive thymocytes could edit their TCR by secondary recombination at the TCRα locus. For this purpose, the VαJα exon of a male-specific TCR was inserted into the TCRα locus followed by Cre-loxP-mediated deletion of the TCRδ locus. In this model, only few thymocytes escaped negative selection by change of specificity, probably through recombination before encounter of autoantigen. In the absence of the restricting MHC element, however, developing thymocytes replaced the inserted TCRα exon efficiently.