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J Immunol. 2015 Aug 1;195(3):934-43. doi: 10.4049/jimmunol.1403038. Epub 2015 Jun 26.

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

Author information

1
Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan; Department of Respiratory Medicine, Allergy, and Rheumatic Disease, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita City, Osaka 565-0871, Japan;
2
Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita City, Osaka 565-0871, Japan; Department of Pathology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan; s_nojima@molpath.med.osaka-u.ac.jp kumanogo@imed3.med.osaka-u.ac.jp.
3
Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Department of Respiratory Medicine, Allergy, and Rheumatic Disease, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita City, Osaka 565-0871, Japan;
4
Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Department of Neurology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
5
Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Department of Respiratory Medicine, Allergy, and Rheumatic Disease, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita City, Osaka 565-0871, Japan; Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
6
Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
7
Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita City, Osaka 565-0871, Japan; Department of Immunology and Regenerative Medicine, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
8
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita City, Osaka 565-0871, Japan; Laboratory of Immunoparasitology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; and.
9
Department of Molecular Neuroimmunology, Institute for Genetic Medicine, Hokkaido University Graduate School of Medicine, Sapporo City, Hokkaido 060-0815, Japan.
10
Department of Pathology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
11
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
12
Department of Immunopathology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan; Department of Respiratory Medicine, Allergy, and Rheumatic Disease, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita City, Osaka 565-0871, Japan; s_nojima@molpath.med.osaka-u.ac.jp kumanogo@imed3.med.osaka-u.ac.jp.

Abstract

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.

PMID:
26116513
PMCID:
PMC4505953
DOI:
10.4049/jimmunol.1403038
[Indexed for MEDLINE]
Free PMC Article

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