UTX is an epigenetic regulator of natural killer cell development and anti-viral effector function.

Abstract

Abstract Natural killer (NK) cells are circulating type 1 innate lymphocytes that protect against viral infection and cancer. While it is now clear that NK cells display distinct epigenetic states during development and activation, the factors that control the epigenetic programming of NK cells during these processes are not well understood. Here, we show that the H3K27me3 histone demethylase UTX epigenetically regulates NK cells in a cell-intrinsic and demethylase-independent manner by regulating the chromatin accessibility of gene loci involved in homeostasis and effector function. As a consequence, mice with NK cell-specific UTX deficiency displayed an increase in peripheral immature NK cell cells that express higher levels of Bcl-2. Furthermore, UTX-deficient NK cells produce lower amounts of interferon (IFN)-γ and Granzyme B following MCMV infection, resulting in increased mortality. These findings reveal UTX as an essential regulator of NK cell homeostatic and effector epigenetic programs. M.I.C. is supported by Ruth L. Kirschstein National Research Service Awards (GM007185 and AI007323), and Whitcome Fellowship from the Molecular Biology Institute at UCLA.