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

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

    Research output: Contribution to journalArticlepeer-review

    101 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

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology

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