E protein control of NKγδT cell development through both generation and function of the stereotypic Vγ1Vδ6.3 TCR

Abstract

ABSTRACTT cell receptor (TCR) signals regulate important developmental transitions through induction of the E protein antagonist, Id3; however, Id3-deficiency produces paradoxical effects on γδ T cell subsets. Here, we show here that Id3-deficiency attenuates the development of Vγ3-expressing γδ T cells, while markedly enhancing the development of Vγ1Vδ6.3-expressing NKγδT cells. Id3-deficiency does so by regulating both the generation of the stereotypic Vγ1Vδ6.3 TCR expressed by NKγδT cells and its capacity to support development. Indeed, we determined that theTrav15segment, which encodes the Vδ6.3 TCR subunit, is directly bound by E proteins that control its expression. Moreover, once expressed, the resulting Vγ1Vδ6.3 TCR in capable of specifying the innate-like NKγδT cell fate in a cell-autonomous and developmentally-unrestricted manner that is restrained by the Id3/E axis. Together, these data indicate that the paradoxical behavior of NKγδT cells in the Id3-deficient setting is entirely determined by its stereotypic Vγ1Vδ6.3 TCR complex.