Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection

Christie Ann McCarl, Sara Khalil, Jian Ma, Masatsugu Ohora, Megumi Yamashita, Jens Roether, Takumi Kawasaki, Amit Jairaman, Yoshiteru Sasaki, Murali Prakriya, Stefan Feske

    Research output: Contribution to journalArticle

    86 Citations (Scopus)

    Abstract

    ORAI1 is the pore-forming subunit of the Ca2+ release-activated Ca2+ (CRAC) channel, which is responsible for store-operated Ca 2+ entry in lymphocytes. A role for ORAI1 in T cell function in vivo has been inferred from in vitro studies of T cells from human immunodeficient patients with mutations in ORAI1 and Orai1-/- mice, but a detailed analysis of T cell-mediated immune responses in vivo in mice lacking functional ORAI1 has been missing. We therefore generated Orai1 knock-in mice (Orai1 KI/KI) expressing a nonfunctional ORAI1-R93W protein. Homozygosity for the equivalent ORAI1-R91W mutation abolishes CRAC channel function in human T cells resulting in severe immunodeficiency. Homozygous Orai1KI/KI mice die neonatally, but Orai1KI/KI fetal liver chimeric mice are viable and show normal lymphocyte development. T and B cells from Orai1 KI/KI mice display severely impaired store-operated Ca2+ entry and CRAC channel function resulting in a strongly reduced expression of several key cytokines including IL-2, IL-4, IL-17, IFN-γ, and TNF-α in CD4+ and CD8+ T cells. Cell-mediated immune responses in vivo that depend on Th1, Th2, and Th17 cell function were severely attenuated in ORAI1-deficient mice. Orai1KI/KI mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wild-type mice. In addition, T cells from Orai1KI/KI mice failed to induce colitis in an adoptive transfer model of inflammatory bowel disease. These findings reaffirm the critical role of ORAI1 for T cell function and provide important insights into the in vivo functions of CRAC channels for T cell-mediated immunity.

    Original languageEnglish
    Pages (from-to)5845-5858
    Number of pages14
    JournalJournal of Immunology
    Volume185
    Issue number10
    DOIs
    Publication statusPublished - Nov 15 2010

    Fingerprint

    Autoimmunity
    Allografts
    T-Lymphocytes
    Lymphocytes
    Th17 Cells
    Th2 Cells
    Mutation
    Th1 Cells
    Interleukin-17
    Adoptive Transfer
    Contact Dermatitis
    Colitis
    Inflammatory Bowel Diseases
    Cellular Immunity
    Interleukin-4
    Interleukin-2
    B-Lymphocytes
    Cytokines
    Skin
    Liver

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology

    Cite this

    McCarl, C. A., Khalil, S., Ma, J., Ohora, M., Yamashita, M., Roether, J., ... Feske, S. (2010). Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. Journal of Immunology, 185(10), 5845-5858. https://doi.org/10.4049/jimmunol.1001796

    Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. / McCarl, Christie Ann; Khalil, Sara; Ma, Jian; Ohora, Masatsugu; Yamashita, Megumi; Roether, Jens; Kawasaki, Takumi; Jairaman, Amit; Sasaki, Yoshiteru; Prakriya, Murali; Feske, Stefan.

    In: Journal of Immunology, Vol. 185, No. 10, 15.11.2010, p. 5845-5858.

    Research output: Contribution to journalArticle

    McCarl, CA, Khalil, S, Ma, J, Ohora, M, Yamashita, M, Roether, J, Kawasaki, T, Jairaman, A, Sasaki, Y, Prakriya, M & Feske, S 2010, 'Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection', Journal of Immunology, vol. 185, no. 10, pp. 5845-5858. https://doi.org/10.4049/jimmunol.1001796
    McCarl, Christie Ann ; Khalil, Sara ; Ma, Jian ; Ohora, Masatsugu ; Yamashita, Megumi ; Roether, Jens ; Kawasaki, Takumi ; Jairaman, Amit ; Sasaki, Yoshiteru ; Prakriya, Murali ; Feske, Stefan. / Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. In: Journal of Immunology. 2010 ; Vol. 185, No. 10. pp. 5845-5858.
    @article{53856d0eae4946c4aea80e5b99d62fae,
    title = "Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection",
    abstract = "ORAI1 is the pore-forming subunit of the Ca2+ release-activated Ca2+ (CRAC) channel, which is responsible for store-operated Ca 2+ entry in lymphocytes. A role for ORAI1 in T cell function in vivo has been inferred from in vitro studies of T cells from human immunodeficient patients with mutations in ORAI1 and Orai1-/- mice, but a detailed analysis of T cell-mediated immune responses in vivo in mice lacking functional ORAI1 has been missing. We therefore generated Orai1 knock-in mice (Orai1 KI/KI) expressing a nonfunctional ORAI1-R93W protein. Homozygosity for the equivalent ORAI1-R91W mutation abolishes CRAC channel function in human T cells resulting in severe immunodeficiency. Homozygous Orai1KI/KI mice die neonatally, but Orai1KI/KI fetal liver chimeric mice are viable and show normal lymphocyte development. T and B cells from Orai1 KI/KI mice display severely impaired store-operated Ca2+ entry and CRAC channel function resulting in a strongly reduced expression of several key cytokines including IL-2, IL-4, IL-17, IFN-γ, and TNF-α in CD4+ and CD8+ T cells. Cell-mediated immune responses in vivo that depend on Th1, Th2, and Th17 cell function were severely attenuated in ORAI1-deficient mice. Orai1KI/KI mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wild-type mice. In addition, T cells from Orai1KI/KI mice failed to induce colitis in an adoptive transfer model of inflammatory bowel disease. These findings reaffirm the critical role of ORAI1 for T cell function and provide important insights into the in vivo functions of CRAC channels for T cell-mediated immunity.",
    author = "McCarl, {Christie Ann} and Sara Khalil and Jian Ma and Masatsugu Ohora and Megumi Yamashita and Jens Roether and Takumi Kawasaki and Amit Jairaman and Yoshiteru Sasaki and Murali Prakriya and Stefan Feske",
    year = "2010",
    month = "11",
    day = "15",
    doi = "10.4049/jimmunol.1001796",
    language = "English",
    volume = "185",
    pages = "5845--5858",
    journal = "Journal of Immunology",
    issn = "0022-1767",
    publisher = "American Association of Immunologists",
    number = "10",

    }

    TY - JOUR

    T1 - Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection

    AU - McCarl, Christie Ann

    AU - Khalil, Sara

    AU - Ma, Jian

    AU - Ohora, Masatsugu

    AU - Yamashita, Megumi

    AU - Roether, Jens

    AU - Kawasaki, Takumi

    AU - Jairaman, Amit

    AU - Sasaki, Yoshiteru

    AU - Prakriya, Murali

    AU - Feske, Stefan

    PY - 2010/11/15

    Y1 - 2010/11/15

    N2 - ORAI1 is the pore-forming subunit of the Ca2+ release-activated Ca2+ (CRAC) channel, which is responsible for store-operated Ca 2+ entry in lymphocytes. A role for ORAI1 in T cell function in vivo has been inferred from in vitro studies of T cells from human immunodeficient patients with mutations in ORAI1 and Orai1-/- mice, but a detailed analysis of T cell-mediated immune responses in vivo in mice lacking functional ORAI1 has been missing. We therefore generated Orai1 knock-in mice (Orai1 KI/KI) expressing a nonfunctional ORAI1-R93W protein. Homozygosity for the equivalent ORAI1-R91W mutation abolishes CRAC channel function in human T cells resulting in severe immunodeficiency. Homozygous Orai1KI/KI mice die neonatally, but Orai1KI/KI fetal liver chimeric mice are viable and show normal lymphocyte development. T and B cells from Orai1 KI/KI mice display severely impaired store-operated Ca2+ entry and CRAC channel function resulting in a strongly reduced expression of several key cytokines including IL-2, IL-4, IL-17, IFN-γ, and TNF-α in CD4+ and CD8+ T cells. Cell-mediated immune responses in vivo that depend on Th1, Th2, and Th17 cell function were severely attenuated in ORAI1-deficient mice. Orai1KI/KI mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wild-type mice. In addition, T cells from Orai1KI/KI mice failed to induce colitis in an adoptive transfer model of inflammatory bowel disease. These findings reaffirm the critical role of ORAI1 for T cell function and provide important insights into the in vivo functions of CRAC channels for T cell-mediated immunity.

    AB - ORAI1 is the pore-forming subunit of the Ca2+ release-activated Ca2+ (CRAC) channel, which is responsible for store-operated Ca 2+ entry in lymphocytes. A role for ORAI1 in T cell function in vivo has been inferred from in vitro studies of T cells from human immunodeficient patients with mutations in ORAI1 and Orai1-/- mice, but a detailed analysis of T cell-mediated immune responses in vivo in mice lacking functional ORAI1 has been missing. We therefore generated Orai1 knock-in mice (Orai1 KI/KI) expressing a nonfunctional ORAI1-R93W protein. Homozygosity for the equivalent ORAI1-R91W mutation abolishes CRAC channel function in human T cells resulting in severe immunodeficiency. Homozygous Orai1KI/KI mice die neonatally, but Orai1KI/KI fetal liver chimeric mice are viable and show normal lymphocyte development. T and B cells from Orai1 KI/KI mice display severely impaired store-operated Ca2+ entry and CRAC channel function resulting in a strongly reduced expression of several key cytokines including IL-2, IL-4, IL-17, IFN-γ, and TNF-α in CD4+ and CD8+ T cells. Cell-mediated immune responses in vivo that depend on Th1, Th2, and Th17 cell function were severely attenuated in ORAI1-deficient mice. Orai1KI/KI mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wild-type mice. In addition, T cells from Orai1KI/KI mice failed to induce colitis in an adoptive transfer model of inflammatory bowel disease. These findings reaffirm the critical role of ORAI1 for T cell function and provide important insights into the in vivo functions of CRAC channels for T cell-mediated immunity.

    UR - http://www.scopus.com/inward/record.url?scp=78650653524&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=78650653524&partnerID=8YFLogxK

    U2 - 10.4049/jimmunol.1001796

    DO - 10.4049/jimmunol.1001796

    M3 - Article

    C2 - 20956344

    AN - SCOPUS:78650653524

    VL - 185

    SP - 5845

    EP - 5858

    JO - Journal of Immunology

    JF - Journal of Immunology

    SN - 0022-1767

    IS - 10

    ER -