Vitamin D and the Vitamin D Receptor regulate development and function of the immune system
Restricted (Penn State Only)
- Author:
- Arora, Juhi
- Graduate Program:
- Pathobiology (PHD)
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 26, 2022
- Committee Members:
- Robert Paulson, Major Field Member
Connie Rogers, Outside Unit & Field Member
Margherita Cantorna, Chair & Dissertation Advisor
Anthony Paul Schmitt, Professor in Charge/Director of Graduate Studies
Troy Sutton, Major Field Member - Keywords:
- vitamin D
influenza
immunity
hematopoiesis - Abstract:
- Active vitamin D ligand, 1alpha,25-dihydroxyvitaminD (1,25D), binds to the vitamin D receptor (VDR), and the ligand-activated complex further regulates transcription of various genes within the target cell. Thus, cells that express the VDR are vitamin D targets. VDR is expressed in immune cells including dendritic cells, macrophages, neutrophils, T cells and B cells. Danger signals such as lipopolysaccharide (LPS), interferon (IFN)-gamma and activation of T and B cells have been shown to regulate the expression of the VDR, implicating its role in modulating immunity. VDR polymorphisms and vitamin D deficiency in humans have been associated with the increased risk of autoimmune diseases such as inflammatory bowel diseases (IBD) and higher susceptibility to both bacterial and viral infections. Identification of vitamin D targets in the immune system and modifying the host immune response through regulation of vitamin D levels is of great clinical significance. We utilized a novel transgenic reporter mouse to lineage trace immune cells that express the VDR. Our data show that both innate (macrophages, monocytes, neutrophils) and adaptive (B and T cells) splenic immune cells expressed tdTomato. Innate lymphoid cells (ILC) 1 and 3 in lungs, small intestine, and colon expressed tdTomato while ILC2 cells did not. Bone marrow (BM) hematopoietic progenitors and thymic T cell progenitors were predominately positive for tdTomato. Peripheral immune cells and their developmental progenitors are tdTomato+ and therefore targets of vitamin D. We sorted tdTomato+ and tdTomato- T cells and studied their response in vitro. Activated tdTomato- T cells did not become tdTomato+, the tdTomato- T cells proliferated faster and produced more IFN-gamma as compared to tdTomato+ T cells. Thus, tdTomato+ and tdTomato- T cells are functionally distinct. Due to the high expression of tdTomato noted in BM progenitors, we further wanted to investigate whether VDR+ and VDR progenitors can be detected earlier in development. tdTomato expression was found in the fetal liver and fetal thymus at embryonic (E) day E15.5. Maternal vitamin D deficiency affected the frequency of fetal hematopoietic progenitors and tdTomato expression, suggesting that the availability of maternal 25-hydroxyvitaminD is needed for fetal liver hematopoiesis and thymopoiesis. Vitamin D deficiency also affected the frequency of tdTomato+ T cells in the spleen and ILCs in the lungs of mice post-birth, highlighting that VDR+ lineage continues to develop after birth. VDR knockout (KO) embryos showed fewer hematopoietic progenitors, while VDR KO adult mice had more hematopoietic progenitors. The effects of vitamin D deficiency (D-) and oral supplementation with vitamin D3 (cholecalciferol) on the outcomes of H1N1 influenza and SARS-CoV-2 infection in animal models was determined. D- mice experienced higher respiratory distress post H1N1 infection. Mice with deletion of Cyp27B1 gene and inability to produce 1,25D had decreased survival post H1N1 infection. SARS-CoV-2 infection induced the expression of vitamin D related genes in the lungs of infected mice. High dose vitamin D3 supplementation reduced lung inflammation in mice infected with SARS-CoV-2. Thus, vitamin D and vitamin D receptor play important roles in development and function of the immune system.