title: mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells.
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.
authors.affiliation: 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;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.affiliation: 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;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishide
authors.affiliation: 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;
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.affiliation: 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;
authors.forename: Hyota
authors.initials: H
authors.lastname: Takamatsu
authors.affiliation: 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;
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.affiliation: 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;
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.affiliation: 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;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: 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;
authors.forename: Keiko
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: 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;
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: 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;
authors.forename: Takashi
authors.initials: T
authors.lastname: Hosokawa
authors.affiliation: 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;
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toyofuku
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Ohshima
authors.affiliation: Department of Molecular Neuroimmunology, Institute for Genetic Medicine, Hokkaido University Graduate School of Medicine, Sapporo City, Hokkaido 060-0815, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.affiliation: 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.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Neuroimmunology, Institute for Genetic Medicine, Hokkaido University Graduate School of Medicine, Sapporo City, Hokkaido 060-0815, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
authors.forename: Eiichi
authors.initials: E
authors.lastname: Morii
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan;
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.affiliation: 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000096:biosynthesis; D053804:Granzymes / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D052899:Pore Forming Cytotoxic Proteins / Q000096:biosynthesis; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D039961:Semaphorins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C519231:Plxnb2 protein, mouse; D052899:Pore Forming Cytotoxic Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C534721:Sema4A protein, mouse; D039961:Semaphorins; D014409:Tumor Necrosis Factor-alpha; C483886:perforin, mouse; D007371:Interferon-gamma; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D053804:Granzymes; C509214:Gzmb protein, mouse