Control of Colitogenic Th17 cells by Vitamin D Receptor Signaling

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PROJECT SUMMARY Vitamin D (Vit D) deficiency is estimated to affect over 1 billion people worldwide and is now considered a global health crisis. In addition to maintaining calcium homeostasis and bone health, Vit D plays an important role in regulating adaptive immunity. Low Vit D levels correlate with various immune-mediated diseases, including inflammatory bowel disease (IBD), while Vit D signaling through the vitamin D receptor (VDR) has been linked to immune tolerance. Central to IBD pathogenesis is the dysregulation of proinflammatory Th17 cells, a subset of CD4 T cells that are characterized by their production of interleukin-17A (IL-17A). While these cells normally contribute to homeostasis at mucosal barrier sites, Th17 cells are pathogenic in IBD. We have shown that VDR is upregulated during Th17 differentiation and treatment with Vit D inhibits Th17 production of proinflammatory cytokines (e.g., IL-17A) in favor of the immunosuppressive cytokine, interleukin-10 (IL-10). How Vit D treatment modulates the Th17 response is unclear. To define its mechanism of action, we have generated two complementary murine models that have VDR reporter activity and are conditional knockouts for the VDR ligand binding domain (LBD). Based on our preliminary data, we propose that VDR signaling directly antagonizes activity of the central transcription factor of Th17 cells, RORgt, to negatively regulate Th17 development and function—thereby modulating colitis pathogenicity. In this proposal, we will use our novel transgenic models to determine whether there is heterogeneity of VDR expression within Th17 populations and whether ligand binding by VDR is essential for its actions in limiting Th17 pathogenicity in colitis. Improving our understanding of how this pathway can modulate Th17 function to protect against immune-mediated diseases, such as IBD, will have broad-reaching implications on patient intestinal health and therapy. The proposed training plan for Blake Frey is sponsored by his mentor, Dr. Casey Weaver. The overall goal of the training plan is to provide the PI with a strong foundation for a successful career as a physician-scientist. A project that is clinically relevant, while focused on a fundamental mechanism of disease pathogenesis, represents the ideal training opportunity for an aspiring physician-scientist. As molecular information becomes more integral to patient care, the ability to understand and interpret these types of data will be essential. Providing Blake with the skills to understand the clinical influence of environmental factors on gastrointestinal immune function will enable him to expand our understanding and application of molecular processes to further understand disease and personalize patient therapy. Included in the training plan are experiences that will help the PI: 1) gain competence in a variety of techniques that integrate immunogenetics and bioinformatics; 2) develop hypothesis-driven research; 3) present data in an oral and written format; 4) effectively integrate research and the clinic; 5) collaborate with other scientists; and 6) responsibly conduct research.