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Arf1 and Arf6 Synergistically Maintain Survival of T Cells during Activation

Mami Sumiyoshi, Yui Kotani, Yuki Ikuta, Kazutomo Suzue, Madoka Ozawa, Tomoya Katakai, Taketo Yamada, Takaya Abe, Kana Bando, Shigeo Koyasu, Yasunori Kanaho, Toshio Watanabe and Satoshi Matsuda
J Immunol January 15, 2021, 206 (2) 366-375; DOI: https://doi.org/10.4049/jimmunol.2000971
Mami Sumiyoshi
*Department of Cell Signaling, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan;
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Yui Kotani
*Department of Cell Signaling, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan;
†Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women’s University, Nara 630-8506, Japan;
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Yuki Ikuta
†Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women’s University, Nara 630-8506, Japan;
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Kazutomo Suzue
‡Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan;
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Madoka Ozawa
§Department of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan;
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Tomoya Katakai
§Department of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan;
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Taketo Yamada
¶Department of Pathology, Saitama Medical University, Iruma-gun, Saitama 350-0495, Japan;
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Takaya Abe
‖Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan;
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Kana Bando
‖Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan;
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Shigeo Koyasu
#Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; and
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Yasunori Kanaho
**Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
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Toshio Watanabe
†Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women’s University, Nara 630-8506, Japan;
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Satoshi Matsuda
*Department of Cell Signaling, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan;
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Key Points

  • Arf1 and Arf6 are dispensable for cytokine secretion in T cells.

  • Arf1 and Arf6 redundantly protect activated naive T cells from apoptosis.

  • Loss of Arf1 and Arf6 in T cells alleviates autoimmune diseases.

Abstract

ADP-ribosylation factor (Arf) family consisting of six family members, Arf1–Arf6, belongs to Ras superfamily and orchestrates vesicle trafficking under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins. It is well established that brefeldin A, a potent inhibitor of ArfGEFs, blocks cytokine secretion from activated T cells, suggesting that the Arf pathway plays important roles in T cell functions. In this study, because Arf1 and Arf6 are the best-characterized members among Arf family, we established T lineage–specific Arf1-deficient, Arf6-deficient, and Arf1/6 double-deficient mice to understand physiological roles of the Arf pathway in the immune system. Contrary to our expectation, Arf deficiency had little or no impact on cytokine secretion from the activated T cells. In contrast, the lack of both Arf1 and Arf6, but neither Arf1 nor Arf6 deficiency alone, rendered naive T cells susceptible to apoptosis upon TCR stimulation because of imbalanced expression of Bcl-2 family members. We further demonstrate that Arf1/6 deficiency in T cells alleviates autoimmune diseases like colitis and experimental autoimmune encephalomyelitis, whereas Ab response under Th2-polarizing conditions is seemingly normal. Our findings reveal an unexpected role for the Arf pathway in the survival of T cells during TCR-induced activation and its potential as a therapeutic target in the autoimmune diseases.

Footnotes

  • This work was supported in part by Japan Society for the Promotion of Science grants-in-aid for scientific research (19K16701 to M.S. and 20K07555 and 20H03776 to S.M.), a Kansai Medical University grant-in-aid for research (to M.S.), the branding program as a world-leading research university on intractable immune and allergic diseases supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Kansai Medical University Molecular Imaging Center of Diseases.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    7-AAD
    7-aminoactinomycin D
    Arf
    ADP-ribosylation factor
    Arf1-KO
    T lineage–specific Arf1-deficient
    Arf1/6-KO
    T lineage–specific Arf1/Arf6 doubly deficient
    Arf6-KO
    T lineage–specific Arf6-deficient
    γc
    common γ-chain
    DP
    double-positive
    EAE
    experimental autoimmune encephalomyelitis
    eF450
    Cell Proliferation Dye eFluor 450
    GAP
    GTPase-activating protein
    GC
    germinal center
    GEF
    guanine nucleotide exchange factor
    IBD
    inflammatory bowel disease
    LP
    lamina propria
    MLN
    mesenteric lymph node
    MOG
    myelin oligodendrocyte glycoprotein
    MS
    multiple sclerosis
    NAC
    N-acetyl-l-cysteine
    PP
    Peyer patch
    ROS
    reactive oxygen species
    SAS
    Sigma Adjuvant System
    SP
    single-positive
    Treg
    regulatory T cell.

  • Received August 24, 2020.
  • Accepted November 12, 2020.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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Arf1 and Arf6 Synergistically Maintain Survival of T Cells during Activation
Mami Sumiyoshi, Yui Kotani, Yuki Ikuta, Kazutomo Suzue, Madoka Ozawa, Tomoya Katakai, Taketo Yamada, Takaya Abe, Kana Bando, Shigeo Koyasu, Yasunori Kanaho, Toshio Watanabe, Satoshi Matsuda
The Journal of Immunology January 15, 2021, 206 (2) 366-375; DOI: 10.4049/jimmunol.2000971

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Arf1 and Arf6 Synergistically Maintain Survival of T Cells during Activation
Mami Sumiyoshi, Yui Kotani, Yuki Ikuta, Kazutomo Suzue, Madoka Ozawa, Tomoya Katakai, Taketo Yamada, Takaya Abe, Kana Bando, Shigeo Koyasu, Yasunori Kanaho, Toshio Watanabe, Satoshi Matsuda
The Journal of Immunology January 15, 2021, 206 (2) 366-375; DOI: 10.4049/jimmunol.2000971
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