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

Xinwei Zhang, Ke Wang, Weijia Zhao, Li Cao, Shusong Zhang, Rong Jin, Xiuyuan Sun, Jie Hao, Xiaojun Huang, Mingzhao Zhu, Hounan Wu, Hongshan Zhao, Qing Ge

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6 Scopus citations


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. 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 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, 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. LTβR-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.

Original languageEnglish
Pages (from-to)395-406
Number of pages12
JournalCellular and Molecular Immunology
Issue number4
StatePublished - 1 Apr 2020
Externally publishedYes


  • Functional maturation
  • MEK/ERK signaling
  • NKT2 cells
  • TRAF3IP3


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