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

摘要

Thymic natural killer T(NKT)2 cells are a subset of invariant NKT cells with PLZF^(hi)GATA3^(hi)IL-4^(+).The differentiation of NKT2 cells is not fully understood.In the present study,we report 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 toα-galactosylceramide.Positive selection and high PLZF expression in CD24^(+)CD44^(−) and CCR7^(+)CD44^(−) immature iNKTs were not affected.Only CD44^(hi)NK1.1^(−) iNKTs in Traf3ip3^(−/−) mice showed reduced expression of Egr2,PLZF,and IL-17RB,decreased proliferation,and reduced IL-4 production upon stimulation.This Egr2 and IL-4 expression was augmented by MEK1/ERK activation in iNKTs,and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation.LT βR-regulated bone marrow-derived nonlymphoid cells in the medullary thymic microenvironment were required for MEK/ERK activation and NKT2 maturation.These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.