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Allele-Specific Regulation of TCR Variable Gene Segment Chromatin Structure¹

Department of Immunology, Duke University Medical Center, Durham, NC 27710

Allelic exclusion of the murine Tcrb locus is imposed at the level of recombination and restricts each cell to produce one functional VDJ rearrangement. Allelic exclusion is achieved through asynchronous V to DJ recombination as well as feedback inhibition that terminates recombination once a functional rearrangement has occurred. Because the accessibility of V gene segment chromatin is diminished as thymocytes undergo allelic exclusion at the CD4^–CD8^– (double-negative) to CD4⁺CD8⁺ (double-positive) transition, chromatin regulation was thought to be an important component of the feedback inhibition process. However, previous studies of chromatin regulation addressed the status of Tcrb alleles using genetic models in which both alleles remained in a germline configuration. Under physiological conditions, developing thymocytes would undergo V to DJ recombination on one or both alleles before the enforcement of feedback. On rearranged alleles, V gene segments that in germline configuration are regulated independently of the Tcrb enhancer are now brought into its proximity. We show in this study that in contrast to V segments on a nonrearranged allele, those situated upstream of a functionally rearranged V segment are contained in active chromatin as judged by histone H3 acetylation, histone H3 lysine 4 (K4) methylation, and germline transcription. Nevertheless, these V gene segments remain refractory to recombination in double-positive thymocytes. These results suggest that a unique feedback mechanism may operate independent of chromatin structure to inhibit V to DJ recombination after the double-negative stage of thymocyte development.

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