Advisor(s)
Casey Weaver
Committee Member(s)
Charles Elson
Hui Hu
Jeremy Day
Rakesh Patel
Robert Welner
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Cellular and Molecular Physiology
Date of Award
1-6-2025
Abstract
Vitamin D3 has long been associated with protection against a myriad of 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. Vitamin D3 signals through another NR, the vitamin D receptor (VDR), to inhibit IL-17A in favor of the immunosuppressive cytokine IL-10; however, the precise mechanisms remain unclear. We developed a novel dual Vdr reporter and conditional knockout mouse model, and for the first time, characterized heterogeneous Vdr expression in Th17 cells, defining the subset of vitamin D3-responsive Th17 cells. Vdr expression was restricted to highly activated Th17 cells, and while activation strength was required, it alone was insufficient to generate Vdr-high Th17 cells. Instead, the induction and function of RORγt were necessary to drive VDR expression. In a feedforward-feedback mechanism, activation by the extrinsic ligand 1,25(OH)2D3 in Vdr-high Th17 cells antagonized the intrinsic RORγt-driven program, leading to a marked reduction in RORγt binding at key RORE sites within Th17 loci. Although 1,25(OH)2D3 enhanced Vdr binding to VDRE sites, this did not directly compete with RORγt but instead facilitated the accessibility and transactivation of a unique Vdr-Th17 gene program. This shifted the Th17 program into a more immunomodulatory state, resulting in the transdifferentiation of Th17 cells into 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.
ProQuest ID
Recommended Citation
Frey, Blake, "Vitamin D Receptor Signaling Antagonizes RorT Signaling To Reprogram Th17 Cells" (2025). All ETDs from UAB. 7257.
https://digitalcommons.library.uab.edu/etd-collection/7257
