The E-Id Protein Axis Specifies Adaptive Lymphoid Cell Identity and Suppresses Thymic Innate Lymphoid Cell Development

Summary Innateand adaptive lymphoid development is orchestratedby the activities of E proteins and their antagonist Id proteins, but how these factors regulate early T cell progenitor (ETP) and innate lymphoid cell(ILC) development remains unclear. Using multiple genetic strategies, we demonstrated that E proteins E2A and HEB acted in synergy in the thymus to establish T cell identity and to suppress the aberrant development of ILCs, including ILC2s and lymphoid-tissue-inducer-like cells. E2A and HEB orchestratedT cell fate and suppressed the ILC transcription signature by activating the expression of genes associated with Notch receptors, T cell receptor(TCR) assembly, and TCR-mediated signaling. E2A and HEB acted in ETPs to establish and maintain a T- cell-lineage-specific enhancer repertoire, including regulatory elements associated with the Notch1 , Rag1 , and Rag2loci. On the basis of these and previous observations, we propose that the E-Id protein axis specifies innateand adaptive lymphoid cell fate.