title: Natural regulatory T cells are resistant to calcium release-activated calcium (CRAC/ORAI) channel inhibition.
abstract: Organ transplant patients are often treated with immunosuppressants, such as the calcineurin phosphatase inhibitor, cyclosporin A, to block T cell-mediated graft rejection. The calcium release-activated calcium (CRAC/ORAI) channels, which act upstream of calcineurin, are essential for calcium entry and CD4(+) T-cell activation. Although cyclosporine A has also been shown to inhibit FoxP3(+) Tregs both in vitro and in vivo, the role of ORAI channel inhibition in natural Tregs (nTregs) or inducible Tregs (iTregs) has not been investigated. We found that, despite inhibition of calcium influx through the ORAI channels, ORAI channel inhibitors were unable to repress FoxP3 expression in mouse and human nTregs, whereas FoxP3 expression was inhibited in iTregs. In contrast, cyclosporin A inhibited FoxP3 expression in both nTregs and iTregs. We also generated mice with a T cell-specific, conditional knockout of ORAI1 and found that the mice have normal nTreg development and suppressive activity. Moreover, iTregs derived from ORAI1 conditional knockout mice develop normally and are still susceptible to ORAI channel inhibition. Our data indicate that unlike CD4(+) T cells and iTregs, nTregs are resistant to ORAI-mediated inhibition. Targeting ORAI channels potentially offers a novel way to inhibit pathologic T cells, while sparing nTreg-mediated tolerance.
authors.affiliation: Inflammation Discovery Therapeutic Area, Hoffmann La-Roche, pRED, Nutley, NJ 07302, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Jin
authors.forename: Jayne
authors.initials: J
authors.lastname: Chin
authors.forename: Christopher
authors.initials: C
authors.lastname: Kitson
authors.forename: John
authors.initials: J
authors.lastname: Woods
authors.forename: Rupal
authors.initials: R
authors.lastname: Majmudar
authors.forename: Valerie
authors.initials: V
authors.lastname: Carvajal
authors.forename: John
authors.initials: J
authors.lastname: Allard
authors.forename: Julie
authors.initials: J
authors.lastname: Demartino
authors.forename: Satwant
authors.initials: S
authors.lastname: Narula
authors.forename: Dori A
authors.initials: DA
authors.lastname: Thomas-Karyat
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016572:Cyclosporine
keywords: FoxP3; ORAI channels; Tregs; cyclosporin A