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

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.