Ets1 represses a T-bet dependent migration program and stabilizes the iNKT1 adhesome

Abstract iNKT cells are innate-like T cells that recognize glycolipids presented on MHCI-like CD1d using a semi-invariant TCR. Upon activation, iNKTs rapidly produce cytokines to direct the adaptive response towards a T H1, T H2 or T H17 response. The transcription factor ETS1 is important for iNKT cell development, but its roles in iNKT function and homeostasis are not well characterized. Utilizing a novel mouse model for targeted deletion of Ets1 in iNKT1s, we show that ETS1 limits expression of T-bet, the signature transcription factor of the iNKT1 lineage. Ets1 Δ/Δhepatic iNKT1 cells upregulated a gene program associated with migration and had reduced expression of LFA-1 and ICAM-1, receptors critical for retention in the liver. Remarkably, Ets1 Δ/Δliver iNKT1s remained tissue resident but no longer required LFA-1/ICAM-1 for retention. Heterozygous deletion of T-bet abrogated expression of multiple migration-associated genes, restored LFA-1 and ICAM-1, and re-established reliance on LFA-1/ICAM-1 for retention. Our data demonstrate that ETS1 controls the mechanisms of hepatic iNKT1 cell residency by limiting a T-bet-dependent migration and adhesion program. Supported by NIH/NIAID grant R01 AI106352