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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Vitamin D is a pleiotropic steroid hormone with immunomodulatory properties. The role of the active metabolite, 1\u03b1,25-dihydroxyvitamin D\n                      <jats:sub>3<\/jats:sub>\n                      (1,25(OH)\n                      <jats:sub>2<\/jats:sub>\n                      vitamin D), in regulating human T-cell effector function and immune checkpoint (IC) pathways remains poorly defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured for five days in presence or absence of 1,25(OH)\n                      <jats:sub>2<\/jats:sub>\n                      vitamin D (10 or 100 nM). IFN-\u03b3 production was assessed by ELISpot assay. Baseline plasma 1,25(OH)\n                      <jats:sub>2<\/jats:sub>\n                      vitamin D levels were measured. IC-related gene expression was evaluated by\u00a0RT-qPCR. Flow cytometry was used to assess the expression of IC, degranulation, and activation markers. FluoroSpot assays were performed to quantify interleukin secretion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      1,25(OH)\n                      <jats:sub>2<\/jats:sub>\n                      vitamin D reduced IFN-\u03b3 expression and secretion independently of baseline circulating 1,25(OH)\n                      <jats:sub>2<\/jats:sub>\n                      vitamin D levels. Dose-specific modulation of IC genes was detected, with increased PDCD1 and CTLA4 mRNA expression. Flow cytometry showed selective modulation within the CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell compartment, with increased PD-1 expression at 10 nM and increased CTLA-4 expression at 100 nM, together with decreased degranulation and activation markers. No significant changes were detected for TIM-3 or TIGIT. In CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, no significant modulation of IC molecules was observed, whereas IL-22 secretion was reduced.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings support an immunomodulatory effect of 1,25(OH)\n                      <jats:sub>2<\/jats:sub>\n                      vitamin D on human CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, with attenuation of effector-associated responses and modulation of checkpoint-associated pathways\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Our results suggest that vitamin D may contribute to the regulation of inflammatory T-cell responses under controlled culture conditions. The functional and therapeutic implications of these observations require further investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1802168","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:34:25Z","timestamp":1783575265000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The 1\u03b1,25-dihydroxyvitamin D3 modulates T cell activation and immune checkpoint pathways in human T cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Lisa","family":"Isdraele Romano","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Catanzaro \u201cMagna Gr\u00e6cia\u201d","place":["Catanzaro, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilenia","family":"Aversa","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical 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