Early TCRα expression generates TCRαγ complexes that signal the DN-to-DP transition and impair development

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Abstract
Clonotypic T cell receptor (TCR) genes undergo ordered rearrangement and expression in the thymus with the result that TCRα and TCRγ proteins are not expressed in the same cell at the same time. Such “TCRα/γ exclusion” is a feature of normal thymocyte differentiation, but it is abrogated in TCR-transgenic mice, which prematurely express transgenic TCRα proteins in early double-negative (DN) thymocytes. We report here that early expression of TCRα proteins results in the formation of TCRαγ complexes that efficiently signal the differentiation of DN into double-positive thymocytes independently of pre-TCR and TCRβ expression. Thus, abrogation of TCRα/γ exclusion by early TCRα expression results in the formation of isotypically mixed TCRαγ complexes whose in vivo signals circumvent TCRβ selection and redirect thymocyte development along an aberrant developmental pathway.