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Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor (\n                    <jats:italic>Vdr<\/jats:italic>\n                    ) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2\/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the\n                    <jats:italic>Ikzf3<\/jats:italic>\n                    -encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.\n                  <\/jats:p>","DOI":"10.7554\/elife.89270","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T07:14:02Z","timestamp":1692947642000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.89270","source":"Crossref","is-referenced-by-count":8,"title":["Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5362-2127","authenticated-orcid":true,"given":"Ayse","family":"Kilic","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04b6nzv94","id-type":"ROR","asserted-by":"publisher"}],"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School","place":["Boston, United 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