MTOR complex signaling through the SEMA4A-plexin B2 axis is required for optimal activation and differentiation of CD8+ T cells

Daisuke Ito, Satoshi Nojima, Masayuki Nishide, Tatsusada Okuno, Hyota Takamatsu, Sujin Kang, Tetsuya Kimura, Yuji Yoshida, Keiko Morimoto, Yohei Maeda, Takashi Hosokawa, Toshihiko Toyofuku, Jun Ohshima, Daisuke Kamimura, Masahiro Yamamoto, Masaaki Murakami, Eiichi Morii, Hiromi Rakugi, Yoshitaka Isaka, Atsushi Kumanogoh

研究成果: Article査読

31 被引用数 (Scopus)

抄録

Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4+ T cell responses, the involvement of mTOR in CD8+ T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8+ T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A-/- CD8+ T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8+ T cell responses were significantly impaired in SEMA4A-/- mice. Furthermore, SEMA4A-/- CD8+ T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8+ T cells. IFN-γ production and mTORC1 activity in SEMA4A-/- CD8+ T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8+ T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8+ T cells, but also reveal a novel link between a semaphorin and mTOR signaling.

本文言語English
ページ(範囲)934-943
ページ数10
ジャーナルJournal of Immunology
195
3
DOI
出版ステータスPublished - 2015 8 1
外部発表はい

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学

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