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

CA McCarl, S Khalil, J Ma, M Oh-Hora… - The Journal of …, 2010 - journals.aai.org
CA McCarl, S Khalil, J Ma, M Oh-Hora, M Yamashita, J Roether, T Kawasaki, A Jairaman…
The Journal of Immunology, 2010journals.aai.org
ORAI1 is the pore-forming subunit of the Ca 2+ release-activated Ca 2+(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 …
Abstract
ORAI1 is the pore-forming subunit of the Ca 2+ release-activated Ca 2+(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 Orai1 KI/KI mice die neonatally, but Orai1 KI/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 Ca 2+ 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. Orai1 KI/KI mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wild-type mice. In addition, T cells from Orai1 KI/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.
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