PMID- 26116513
OWN - NLM
STAT- MEDLINE
DCOM- 20151026
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 195
IP  - 3
DP  - 2015 Aug 1
TI  - mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal 
      Activation and Differentiation of CD8+ T Cells.
PG  - 934-43
LID - 10.4049/jimmunol.1403038 [doi]
AB  - 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-gamma 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.
CI  - Copyright (c) 2015 by The American Association of Immunologists, Inc.
FAU - Ito, Daisuke
AU  - Ito D
AD  - 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;
FAU - Nojima, Satoshi
AU  - Nojima S
AD  - 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.
FAU - Nishide, Masayuki
AU  - Nishide M
AD  - 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;
FAU - Okuno, Tatsusada
AU  - Okuno T
AD  - 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;
FAU - Takamatsu, Hyota
AU  - Takamatsu H
AD  - 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;
FAU - Kang, Sujin
AU  - Kang S
AD  - 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;
FAU - Kimura, Tetsuya
AU  - Kimura T
AD  - 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;
FAU - Yoshida, Yuji
AU  - Yoshida Y
AD  - 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;
FAU - Morimoto, Keiko
AU  - Morimoto K
AD  - 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;
FAU - Maeda, Yohei
AU  - Maeda Y
AD  - 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;
FAU - Hosokawa, Takashi
AU  - Hosokawa T
AD  - 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;
FAU - Toyofuku, Toshihiko
AU  - Toyofuku T
AD  - 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;
FAU - Ohshima, Jun
AU  - Ohshima J
AD  - 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.
FAU - Kamimura, Daisuke
AU  - Kamimura D
AD  - Department of Molecular Neuroimmunology, Institute for Genetic Medicine, Hokkaido 
      University Graduate School of Medicine, Sapporo City, Hokkaido 060-0815, Japan.
FAU - Yamamoto, Masahiro
AU  - Yamamoto M
AD  - 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.
FAU - Murakami, Masaaki
AU  - Murakami M
AD  - Department of Molecular Neuroimmunology, Institute for Genetic Medicine, Hokkaido 
      University Graduate School of Medicine, Sapporo City, Hokkaido 060-0815, Japan.
FAU - Morii, Eiichi
AU  - Morii E
AD  - Department of Pathology, Osaka University Graduate School of Medicine, Suita 
      City, Osaka 565-0871, Japan;
FAU - Rakugi, Hiromi
AU  - Rakugi H
AD  - Department of Geriatric Medicine and Nephrology, Osaka University Graduate School 
      of Medicine, Suita City, Osaka 565-0871, Japan;
FAU - Isaka, Yoshitaka
AU  - Isaka Y
AD  - Department of Geriatric Medicine and Nephrology, Osaka University Graduate School 
      of Medicine, Suita City, Osaka 565-0871, Japan;
FAU - Kumanogoh, Atsushi
AU  - Kumanogoh A
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150626
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Fasl protein, mouse)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Plxnb2 protein, mouse)
RN  - 0 (Pore Forming Cytotoxic Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Sema4A protein, mouse)
RN  - 0 (Semaphorins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (perforin, mouse)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.21.- (Granzymes)
RN  - EC 3.4.21.- (Gzmb protein, mouse)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/cytology/*immunology
MH  - Cell Differentiation/immunology
MH  - Cell Proliferation
MH  - Fas Ligand Protein/biosynthesis
MH  - Granzymes/biosynthesis
MH  - Interferon-gamma/biosynthesis
MH  - Listeria monocytogenes/immunology
MH  - Listeriosis/immunology
MH  - Lymphocyte Activation/*immunology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Multiprotein Complexes/*immunology/metabolism
MH  - Nerve Tissue Proteins/genetics/*physiology
MH  - Pore Forming Cytotoxic Proteins/biosynthesis
MH  - Protein Binding/immunology
MH  - RNA Interference
MH  - RNA, Small Interfering
MH  - Recombinant Proteins/genetics/pharmacology
MH  - Semaphorins/genetics/*physiology
MH  - Signal Transduction/immunology
MH  - TOR Serine-Threonine Kinases/*immunology/metabolism
MH  - Tumor Necrosis Factor-alpha/biosynthesis
PMC - PMC4505953
EDAT- 2015/06/28 06:00
MHDA- 2015/10/27 06:00
PMCR- 2015/06/26
CRDT- 2015/06/28 06:00
PHST- 2014/12/05 00:00 [received]
PHST- 2015/05/22 00:00 [accepted]
PHST- 2015/06/28 06:00 [entrez]
PHST- 2015/06/28 06:00 [pubmed]
PHST- 2015/10/27 06:00 [medline]
PHST- 2015/06/26 00:00 [pmc-release]
AID - jimmunol.1403038 [pii]
AID - ji_1403038 [pii]
AID - 10.4049/jimmunol.1403038 [doi]
PST - ppublish
SO  - J Immunol. 2015 Aug 1;195(3):934-43. doi: 10.4049/jimmunol.1403038. Epub 2015 Jun 
      26.