ORAI2 modulates store-operated calcium entry and T cell-mediated immunity

Martin Vaeth, Jun Yang, Megumi Yamashita, Isabelle Zee, Miriam Eckstein, Camille Knosp, Ulrike Kaufmann, Peter Karoly Jani, Rodrigo S. Lacruz, Veit Flockerzi, Imre Kacskovics, Murali Prakriya and Stefan Feske ()
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Martin Vaeth: Experimental Pathology Program, New York University School of Medicine
Jun Yang: Experimental Pathology Program, New York University School of Medicine
Megumi Yamashita: Northwestern University, Feinberg School of Medicine
Isabelle Zee: Experimental Pathology Program, New York University School of Medicine
Miriam Eckstein: NYU College of Dentistry, New York University
Camille Knosp: Experimental Pathology Program, New York University School of Medicine
Ulrike Kaufmann: Experimental Pathology Program, New York University School of Medicine
Peter Karoly Jani: ImmunoGenes
Rodrigo S. Lacruz: NYU College of Dentistry, New York University
Veit Flockerzi: Experimental and Clinical Pharmacology and Toxicology, School of Medicine, Saarland University
Imre Kacskovics: ImmunoGenes
Murali Prakriya: Northwestern University, Feinberg School of Medicine
Stefan Feske: Experimental Pathology Program, New York University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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 T cell 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.

Date: 2017
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DOI: 10.1038/ncomms14714

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