Dose-Dependent Requirements for ETS1 in Invariant Natural Killer T (iNKT) Cell Development

Abstract

Abstract iNKT cells are innate-like T cells that use an invariant T cell receptor to recognize glycolipids presented by the non-classical major histocompatibility protein CD1d. Upon recognition, iNKTs rapidly produce cytokines that stimulate innate cells to produce cytokines and prime adaptive cells for activation upon antigenic stimulation. Studies in Ets1 germline-deficient mice showed that the transcription factor ETS1 is required for the development of CD4+ NK1.1+ NKT cells. Development of CD1d tetramers and the recent elucidation of multiple effector iNKT cell subsets has improved our understanding of NKT cell development and function, and revealed that CD4+ NK1.1+ iNKT cells are a minor subset of total NKTs. Using conditional deletion for Ets1 in thymocytes, we show that Ets1 is a dose dependent regulator of all iNKT cells and appears to be particularly important for development of interferon-g-producing iNKT1 cells. Deletion of Ets1 in developing iNKT1 cells using Tbx21Cre demonstrated the critical role of ETS1 in this iNKT cell effector subset. Our findings set the stage for future studies focused on the molecular mechanism by which ETS1 controls iNKT cell development and function.