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 - Oh-Hora, 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 -