Biallelic T cell receptor rearrangement enhances the efficiency of thymocyte development and positive selection. (HEM4P.234)

Abstract

Abstract Biallelic rearrangement of TCR loci has been proposed to increase the likelihood of productive gene rearrangement, thereby promoting thymocyte survival. When allelic exclusion is incomplete, this process also results in dual TCR-expressing T cells, which may increase repertoire diversity, but may also increase autoreactive potential. We investigated the effects of biallelic TCR gene rearrangement by comparing wildtype (wt) T cells to those from mice hemizygous for the genes encoding TCR α, TCR β, or both. Using bone marrow chimera competition assays we found that Tcrb hemizygous thymocytes were impaired in the DN1 to DN2 transition relative to wt cells. In addition, Tcrb hemizygous mice exhibited a higher frequency of T cells committed to the γδ lineage. Bone marrow chimera competition assays revealed a dramatic increase in the ratio of wt thymocytes to Tcra hemizygous thymocytes between the pre-selection and post-selection DP compartments, demonstrating that biallelic Tcra rearrangement increases the rate of positive selection. Despite their impairments in thymocyte development, mice hemizygous for both Tcra and Tcrb generated polyclonal T cell repertoires similar to wt mice as assessed by numbers of antigen-specific naïve T cells, responses to multiple self and foreign antigens, and TCRβ sequence diversity. Thus, biallelic rearrangement of Tcra and Tcrb loci enhances the efficiency of thymocyte development, but is not necessary for normal TCR repertoire diversification.