Abstract
Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels is critical for lymphocyte function and immune responses. CRAC channels are hexamers of ORAI proteins that form the channel pore, but the contributions of individual ORAI homologues to CRAC channel function are not well understood. Here we show that deletion of Orai1 reduces, whereas deletion of Orai2 increases, SOCE in mouse T cells. These distinct effects are due to the ability of ORAI2 to form heteromeric channels with ORAI1 and to attenuate CRAC channel function. The combined deletion of Orai1 and Orai2 abolishes SOCE and strongly impairs Tcell function. In vivo, Orai1/Orai2 double-deficient mice have impaired T cell-dependent antiviral immune responses, and are protected from T cell-mediated autoimmunity and alloimmunity in models of colitis and graft-versus-host disease. Our study demonstrates that ORAI1 and ORAI2 form heteromeric CRAC channels, in which ORAI2 fine-tunes the magnitude of SOCE to modulate immune responses.
Original language | English (US) |
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Article number | 14714 |
Journal | Nature communications |
Volume | 8 |
DOIs | |
State | Published - Mar 15 2017 |
Funding
This work was funded by NIH Grants AI097302 (to S.F.) and GM114210 and NS057499 (to M.P.), postdoctoral fellowships VA 882/1-1 (to M.V.) and KA 4083/2-1 (to U.K.) by the Deutsche Forschungsgemeinschaft (DFG) and DFG Grants FL 153/10-1 and SFB894 (to V.F.). The histopathology and cell sorting core facilities at NYU School of Medicine are supported in part by NIH Grant UL1TR00038 from the National Center for Advancing Translational Sciences (NCATS) and by a grant (P30CA016087) to the Laura and Isaac Perlmutter Cancer Center. Analysis of murine Orai1, Orai2 and Orai3 mRNA expression was accomplished in part using data from the ImmGen Consortium. Orai1fl/fl mice and 2C1.1 antibody were kindly provided by Dr H. McBride (Amgen Inc.). Embryonic stem cells used to generate Orai2LacZ+ mice were generated by the trans-NIH Knock-Out Mouse Project (KOMP) and obtained from the KOMP Repository (http://www.komp.org), which were funded by NIH Grants U01HG004085 (to Velocigene at Regeneron Inc.) and U42RR024244 (to the KOMP Repository at UC Davis and CHORI).
ASJC Scopus subject areas
- General Physics and Astronomy
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology