Ets1 Regulates the Expression of ICOS and Controls the Maturation, Homeostasis, and Function of Invariant NKT Cells

The transcription factor Ets1 is essential for the development of iNKT cells. However, its detailed role and mechanism of action are unknown. We used two genetic approaches to generate iNKT cells with either impaired Ets1 activity or deficient in Ets1. Here we show that Ets1 is dispensable for the expression of Va14Ja18 TCR and thymic selection of iNKT cells, but is essential for the maturation of post-selected iNKT cells.  This function of Ets1 can be partly compensated by a Vα14Jα18 TCR transgene and is independent of its N-terminal Pointed domain. Ets1 also promotes the production of type 1 and type 2 cytokines but suppresses the expression of IL-17A by a Pointed domain-dependent mechanism. Furthermore, Ets1 directly transactivates ICOS and Ets1-deficient peripheral iNKT cells are prone to apoptosis. Taken together, Ets1 has Pointed domain-dependent and independent functions in iNKT cells and regulates their peripheral survival by promoting the expression of ICOS.