STAT3 regulates iNKT cell development and function but is not required for NKT17 cell development (LYM6P.715)

Abstract Signal transducer and activator of transcription 3 (STAT3) controls the expansion of T help 17 cell (Th17) lineage through induction of transcription factor orphan nuclear receptor (RORγt). CD1d-restricted invariant natural killer T (iNKT) cells are potent regulators of diverse immune responses and have three sublineages, NKT1, NKT2, and NKT17 cells. However, it still remains unclear how to regulate NKT17 cell development. Using lymphocyte-specific STAT3 hyperactivation mice, we found that overactivation of STAT3 universally suppressed iNKT cell cytokine secretion, including IL-17, while it enhanced conventional Th17 cell development. Consistently, STAT3 hyperactivation reduces the RORγt expression of iNKT cells. Surprisingly, bone marrow chimera experiments revealed that STAT3 overactivation disturbed iNKT cell maturation and increased IFNγ- and IL-4-secreting iNKT cells while it did not affect IL-17 secreting iNKT cells and did not alter RORγt expression of iNKT cells. Our results demonstrate that STAT3 regulates the development and function of iNKT cells, but unlike conventional Th17 cells, STAT3 is not required for IL-17 production and RORγt expression in iNKT cells.