mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8(+) T Cells

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

来源：The Journal of Immunology, 2015, 195(3): 934-943.

DOI：10.4049/jimmunol.1403038

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-gamma and TNF-alpha 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-g 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.

• 出版日期2015-8-1
• 单位河北医科大学