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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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. 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
Volume17
Issue number4
DOIs
StatePublished - 1 Apr 2020
Externally publishedYes

Keywords

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

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