Project Summary Invariant Natural Killer T (iNKT) cells are T lymphocytes that express a semi-invariant T cell receptor (TCR) and exist in a primed effector state capable of making numerous cytokines within minutes after activation. iNKT1 cells develop in the thymus and migrate as immature cells to peripheral lymphoid and non-lymphoid organs where they reside as tissue-resident sentinels that protect against invading pathogens. Here we describe the transcription factor Ets1 as a central regulator of the development, adhesion, migration, and NK cell-associated gene programs of iNKT1 cells that control their tissue residency, localization, and function. We propose experiments to investigate the relevance of these programs to iNKT1 cell development, trafficking, location and function as well as experiments to identify the molecular basis for Ets1- mediated regulation of these programs in the thymus, liver and spleen. Given the conservation of tissue residency and adhesion programs across lymphocytes, we propose that our data will provide not only significant insight into the mechanisms controlling iNKT1 cell location but also in other innate and adaptive lymphocytes.