TRAF3IP3 at the trans-Golgi network regulates NKT2 maturation via MEK/ERK signaling pathway

Abstract

Abstract Thymic natural killer T (NKT)2 cells are a subset of invariant NKT cells with PLZFhiGATA3hiIL-4+. The differentiation of NKT2 cells is not fully understood. We report in the present study an important role of TRAF3-interacting protein 3 (TRAF3IP3) in the functional maturation and expansion of committed NKT2s in thymic medulla. Mice with T cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells, decreased IL-4 producing peripheral iNKTs, and defects in response to α-galactosylceramide. Positive selection and high PLZF expression in CD24+CD44− and CCR7+CD44− immature iNKTs were not affected. Only CD44hiNK1.1− iNKTs in Traf3ip3−/− mice showed reduced expression of Egr2, PLZF, IL-17RB, decreased proliferation, and decreased IL-4 production upon stimulation. Such Egr2 and IL-4 expression were augmented by MEK1/ERK activation in iNKTs and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation. These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.