{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:47:20Z","timestamp":1790711240337,"version":"4.1.0"},"posted":{"date-parts":[[2020,7,19]]},"group-title":"Immunology","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2020,7,19]],"date-time":"2020-07-19T00:00:00Z","timestamp":1595116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2020,7,19]]},"abstract":"<jats:p>\n                  Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner\n                  <jats:sup>1,2<\/jats:sup>\n                  . Excessive complement and IFN-\u03b3-associated responses are known drivers of immunopathogenesis\n                  <jats:sup>3<\/jats:sup>\n                  and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection\n                  <jats:sup>4<\/jats:sup>\n                  . The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-\u03b3 producing CD4\n                  <jats:sup>+<\/jats:sup>\n                  T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-\u03b3\n                  <jats:sup>+<\/jats:sup>\n                  Th1 cells to suppressive IL-10\n                  <jats:sup>+<\/jats:sup>\n                  Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells, generating superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor\n                  <jats:sup>5\u20137<\/jats:sup>\n                  . Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells were defective in IL-10 production. As proof-of-concept, we show that CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4\n                  <jats:sup>+<\/jats:sup>\n                  BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyperinflammation in severe COVID-19.\n                <\/jats:p>","DOI":"10.1101\/2020.07.18.210161","type":"posted-content","created":{"date-parts":[[2020,7,19]],"date-time":"2020-07-19T23:45:10Z","timestamp":1595202310000},"source":"Crossref","is-referenced-by-count":19,"title":["An autocrine Vitamin D-driven Th1 shutdown program can be exploited for 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