Aberrant generation and function of natural killer T (NKT) cell in absence of Utx and Jmjd3

Abstract Histone H3 lysine 27 trimethylation (H3K27Me3) demethylases Jmjd3 and Utx, the epigenetic regulators, affects transcription and cell differentiation. But their specific roles in invariant natural killer T (NKT) cells development, maturation and function remain to be explored. Using T cell-specific Utx and Jmjd3 double knock out (DKO) mouse model, we identified that Utx and Jmjd3 deletion results in profound impairment in NKT numbers and maturation of both thymic and peripheral immune organs. DKO thymus NKT cells showed dramatic blockade of maturation at stage 0 and stage 1. Defective expression of Slamf1 (CD150) in DKO CD69+DP thymocytes was identified, suggesting an interrupted DP selecting process. Additionally, we found the impaired expression of PLZF, Tbet, ICOS in DKO NKT cells, which is consistent with the defective NKT sublineage development in those mice. Furthermore, DKO iNKT cells showed significantly defective IFN-r, IL-4 and IL-17 production upon activation. Bone marrow chimera experiment confirmed the major defects of NKT cell development, maturation and function in DKO mice are cell autonomous. Altogether, our present study demonstrates critical contribution of Utx and Jmjd3 in NKT cell development, lineage differentiation and function. Utx and Jmjd3 related epigenetic landscape and gene expression network involved in NKT cell development and function regulation are currently under investigation.