{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:13:38Z","timestamp":1790356418240,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T00:00:00Z","timestamp":1657584000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>NFATs and FOXP3 are linked with impaired regulatory T\u2010cells (Tregs) in generalized vitiligo (GV). To elucidate calcium mediated NFATc1 signalling pathway and its effect on Treg suppressive capacity in GV. Calcium levels, calcineurin, NFATc1 and GSK\u20103\u03b2 activity and cell proliferation were assessed in 52 GV patients and 50 controls by calcium assay kit, calcineurin phosphatase assay kit, TransAM NFATc1 kit, GSK\u20103\u03b2 ELISA and BrdU cell proliferation assay. Transcripts (<jats:italic>CNB<\/jats:italic>, <jats:italic>CAM<\/jats:italic>, <jats:italic>GSK3B<\/jats:italic>, <jats:italic>DYRK1A<\/jats:italic> and calcium channel genes) and protein (IFN\u2010\u03b3, IL\u201010 and TGF\u2010\u03b2) expressions were assessed by qPCR and ELISA, respectively. Reduced plasma and intracellular Tregs calcium levels and <jats:italic>ORAI1<\/jats:italic> transcripts suggested altered calcium homeostasis in GV Tregs (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.00387, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.0048, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), which led to decreased calcineurin and NFATc1 activity in GV Tregs (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0299, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). <jats:italic>CNB<\/jats:italic> and <jats:italic>CAM<\/jats:italic> transcripts were reduced in GV Tregs (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.0004). GSK\u20103\u03b2 activity, <jats:italic>GSK3B<\/jats:italic> and <jats:italic>DYRK1A<\/jats:italic> transcripts significantly increased in GV Tregs (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0134, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001 and <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Plasma (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0225, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.032) and intracellular Treg (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0035, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.005) calcium levels, calcineurin (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.001) and NFATc1 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.001, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) activity and <jats:italic>ORAI1<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0093, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), <jats:italic>CAM<\/jats:italic> and <jats:italic>CNB<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0214) transcripts significantly decreased in active vitiligo (AV) and severe GV (sGV) Tregs. Calcium treatment significantly increased intracellular calcium and <jats:italic>ORAI1<\/jats:italic> transcripts in GV Tregs (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0042, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.0035). Moreover, calcium treatment enhanced calcineurin and NFATc1 activity in GV Tregs (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0128, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Remarkably, calcium treatment increased Treg mediated suppression of CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T\u2010cells (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.015, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.006) in GV and increased Tregs associated cytokines: IL\u201010 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0323, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.009), TGF\u2010\u03b2 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0321, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.01) and decreased IFN\u2010\u03b3 production (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.001, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.016) by CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T\u2010cells. Intracellular calcium levels positively correlated with calcineurin (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.83; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and NFATc1 (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.61; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) activity, suggesting the enhanced Treg immunosuppressive capacity after calcium treatment. Our study for the first time suggests that reduced plasma calcium and <jats:italic>ORAI1<\/jats:italic> transcripts are linked to calcium uptake defects in Tregs, which leads to reduced calcineurin and NFATc1 activation, thereby contributing to decreased Tregs immunosuppressive capacity in GV. Elevated GSK\u20103\u03b2 activity and <jats:italic>GSKB<\/jats:italic> and <jats:italic>DYRK1A<\/jats:italic> transcripts are involved in reduced NFATc1 activity in GV Tregs. Overall, the study suggests that calcium\u2010NFATc1\u2010signalling pathway is likely to be involved in defective Tregs function and can be implicated for development of effective Treg mediated therapeutics for GV.<\/jats:p>","DOI":"10.1111\/imm.13538","type":"journal-article","created":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T04:49:28Z","timestamp":1656305368000},"page":"314-327","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Calcium controlled NFATc1 activation enhances suppressive capacity of regulatory T cells isolated from generalized vitiligo patients"],"prefix":"10.1111","volume":"167","author":[{"given":"Prashant S.","family":"Giri","sequence":"first","affiliation":[{"name":"C. G. 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