Vitamin D receptor signaling antagonizes rorgt signaling to reprogram Th17 cells

Summary: Abstract Body: Vitamin D3 deficiency has been associated with susceptibility to autoimmune diseases commonly linked to dysregulation of the T helper 17 (Th17) program. Th17 cells rely on the nuclear receptor (NR) RORγt as the master transcription factor for differentiation and function, establishing a metastate that can drive pro-inflammatory or alternative pathways depending on external cues. The active hormone of vitamin D3, 1a,25(OH)2D3, signals through another NR, the vitamin D receptor (VDR), to inhibit IL-17A in favor of the immunosuppressive cytokine IL-10; however, the mechanism remains unclear. We developed a novel dual Vdr reporter and conditional knockout mouse model and, for the first time, have identified heterogeneous Vdr expression in Th17 cells, defining a subset of vitamin D3-responsive Th17 cells. Expression of Vdr was restricted to the most highly activated Th17 cells and was dependent on RORγt signaling, establishing a feedforward-feedback mechanism wherein activation of Vdr by the extrinsic ligand 1a,25(OH)2D3 antagonized the intrinsic RORγt-driven program, leading to a marked reduction in RORγt binding at key RORE sites within Th17 loci. Although 1a,25(OH)2D3 enhanced Vdr binding to VDRE sites, this did not directly compete with RORγt but instead facilitated the locus accessibility and transactivation of a unique Vdr-Th17 gene program that resulted in the transdifferentiation of Th17 cells into pro-tolerogenic ex-Th17 cells. The antagonistic role of vitamin D3 in limiting reactive Th17 cells offers insight into the strong association between vitamin D and autoimmune disease. Blake Frey¹, Carlene Zindl¹, Casey T. Weaver¹ 1. Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States. Adaptive and Auto-Immunity