Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases

Abstract

It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.

Increased Risk of Vitamin D Deficiency Among HIV-Infected Individuals: A Systematic Review and Meta-Analysis

“…Vitamin D modulates immune responses. Its receptors are expressed on nearly all immune cells, primarily CD8 and CD4 T lymphocytes ( 45 ). In addition to responding to infection, it also prevents the development of autoimmune diseases, such as type 1 diabetes, systemic lupus erythematosus, and inflammatory bowel disease.…”

NCF4 regulates antigen presentation of cysteine peptides by intracellular oxidative response and restricts activation of autoreactive and arthritogenic T cells

“…P4HB catalyzes the formation of 4-hydroxyproline in collagen [ 49 ] while PDIA3 interacts with calcitriol, an active form of vitamin D3, which could regulate gene expression through binding to the nuclear receptor vitamin D receptor (VDR) in cells [ 50 ]. Interestingly, genetic polymorphism of the VDR promoter, which controls VDR expression and T cell activation, is associated with the development of CIA [ 51 ]. Moreover, we could also show that the oxidized P4HB and PDIA3 protein levels were enhanced in day 7 CIA splenocytes from NCF4 [58A] mice.…”

Present therapeutic and diagnostic approaches for SARS-CoV-2 infection

“…Further, it was observed that deficiency of vitamin D3 is associated with increased autoimmunity and enhanced susceptibility to infection ( Aranow, 2011 , Martens et al, 2020 ). Moreover, it was also revealed that vitamin D3 supplements result in elevated T cell levels along with their enhanced activity ( Fernandez Lahore et al, 2020 ). All the preceding discussion makes vitamin D3 an attractive drug to manage COVID-19 disease.…”