Receptor-specific allelic exclusion of TCRVα-chains during development

Abstract

Expression of a single Ag receptor on lymphocytes is maintained via allelic exclusion that generates cells with a clonal receptor repertoire. We show in normal mice and mice expressing functionally rearranged TCRαβ transgenes that allelic exclusion at the TCRα locus is not operational in immature thymocytes, whereas most mature T cells express a single TCRVα- chain. TCRVα allelic exclusion in mature thymocytes is regulated through a CD45 tyrosine phosphatase-mediated signal during positive selection. Using functional and genetic systems for selection of immature double TCRVα+ thymocytes, we show that peptide-specific ligand recognition provides the signal for allelic exclusion, i.e., mature T cells maintain expression of the ligand-specific TCRVα-chain, but lose the nonfunctional receptor. Whereas activation of TCRVβ-chains or CD3ε leads to receptor internalization, TCRVα ligation promotes retention of the TCR on the cell surface. Although both TCRVα- and TCRVβ-chains trigger phosphotyrosine signaling, only the TCRVβ-chain mediates membrane recruitment of the GTPase dynamin. These data indicate that TCRVα-directed signals for positive selection control allelic exclusion in T cells, and that developmental signals can select for single receptor usage.