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Polymorphisms of the vitamin D receptor regulate T cells and T cell dependent inflammatory diseases

ABSTRACT: Complex autoimmune diseases have proven difficult to dissect down to their causative genetic mechanisms. As a result, epidemiological data from different human association studies are often merged to arrive at a working hypothesis. In one of such examples, lack of sun exposure and consequent lower serum vitamin D3 levels has been proposed to increase risk of autoimmunity, attributing vitamin D3 an immune regulatory role. However, conclusive evidence demonstrating its efficacy in treating autoimmune diseases is missing. In this study, we have used a forward genetics approach to positionally identify polymorphic nucleotides controlling T cell-dependent inflammatory diseases using congenic mouse strains. Here, we identify the vitamin D3 receptor (Vdr) as a driver of inflammation. Congenic mice carrying a polymorphic Vdr allele overexpressed the receptor selectively in activated T cells, thereby escaping systemic calcaemic side effects that often constitute a confounding factor in the study of immunomodulation by vitamin D3. Mice overexpressing Vdr in T cells developed more severe collagen-induced arthritis (CIA) and exhibited an enhanced antigen-specific CD4+ T cell response. Deficiency of vitamin D3 completely protected mice from CIA by limiting the activation of antigen-specific T cell responses, and arthritis susceptibility was restored by re-administration of vitamin D3. We demonstrate that vitamin D3 signalling specifically through Vdr predominantly acts to enhance T cell proliferation, thereby contributing to inflammation. In conclusion, our results demonstrate that genetically determined expression of VDR codetermines the pro-inflammatory behaviour of activated T cells. Furthermore, our data suggest that the anti-inflammatory properties of vitamin D3 might be limited by high expression of VDR at the site of inflammation.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell, Lymph Node

SUBMITTER: Pierre Sabatier

LAB HEAD: Roman Zubarev

PROVIDER: PXD019876 | Pride | 2020-09-28

REPOSITORIES: Pride

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

Fernandez Lahore Gonzalo G Raposo Bruno B Lagerquist Marie M Ohlsson Claes C Sabatier Pierre P Xu Bingze B Aoun Mike M James Jaime J Cai Xiaojie X Zubarev Roman A RA Nandakumar Kutty Selva KS Holmdahl Rikard R

Proceedings of the National Academy of Sciences of the United States of America 20200921 40

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 (<i>Vdr</i>) promoter, controlling <i>Vdr</i> 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 effe ...[more]

PMID: 32958661

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Project description:Background: In addition to its canonical functions, vitamin D has been proposed to be an important mediator of the immune system. Despite ample sunshine, vitamin D deficiency is prevalent (> 80%) in the Middle East, resulting in a high rate of supplementation. However, the underlying molecular mechanisms of the specific regimen and potential factors affecting an individual’s response to vitamin D are not well characterized. Objective: To characterize changes in blood transcriptomic and the potential mechanisms associated with vitamin D3 supplementation and response. Design: In this intervention study, one hundred vitamin D-deficient women were given a weekly oral dose (50,000 IU) of vitamin D3 for three months. A high-throughput targeted PCR, composed of 264 genes representing important blood transcriptomic fingerprints in health and disease states, was performed on pre- and post-supplementation blood samples to profile the molecular response to vitamin D3. Multivariate, network, gene ontology, and literature mining analyses were used for the interpretation of the transcriptomic profiling results. Results: We identified 54 differentially expressed genes that were strongly modulated by vitamin D3 supplementation. Network analyses showed significant changes in the immune-related pathways such as TLR4/CD14 and IFN receptors, and catabolic processes related to NFkB, which were subsequently confirmed by gene ontology enrichment analyses. We proposed a model for vitamin D3 response, using the reduced expression of the molecules involved and the receptor-mediated intra-cellular signaling leading to reduce cytokine production. Conclusions: Blood-transcriptomic profiles of vitamin D3 response were generated using a targeted blood gene panel. Vitamin D has a strong effect on the immune system, G-coupled protein receptor signaling, and the ubiquitin system. We highlighted the major molecular changes and biological processes induced by vitamin D3, which will help to further investigate the effectiveness of vitamin D supplementation among individuals in the Middle East.

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