USP22 controls iNKT immunity partially through MED1-mediated suppression of target-specific histone H2A monoubiquitination

Abstract

Abstract The development and functions of CD1d-restricted iNKT cells are critical for both innate and adaptive immunity. While the ubiquitin pathway has been shown to regulate iNKT cell development and functions, the deubiquitinase involved in this process has not been identified. Herein we found that the ubiquitin-specific peptidase 22 (USP22) is highly expressed in iNKT cells during their early developmental stage I. USP22-deficiency blocked the transition from stage I to II during iNKT cell development in a cell-intrinsic manner. In addition, genetic USP22 suppression largely diminishes IL-17-producing iNKT17 and IFN-g-producing iNKT1 differentiation but favors IL-4 producing iNKT2 polarization. In contrast, genetic USP22 suppression did not alter conventional CD4 T cell clonal expansion and differentiation. At the molecular level, USP22 interacts with the Mediator of RNA polymerase II transcription subunit 1 (MED1), a transcription co-activator involved in iNKT cell development. Interestingly, while interacting with MED1, USP22 does not function as a deubiquitinase to suppress MED1 ubiquitination for its stabilization. Instead, USP22 enhances MED1 functions for IL-2Rb and T-bet gene expression through deubiquitinating histone H2A but not H2B mono-ubiquitination. Therefore, our study revealed USP22-mediated histone H2A deubiquitination fine-tunes MED1 transcriptional activation as a previously unappreciated molecular mechanism to control iNKT development and functions.