PXD019876

PXD019876 is an original dataset announced via ProteomeXchange.

Title	Polymorphisms of the vitamin D receptor regulate T cells and T cell dependent inflammatory diseases
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-09-28
AnnouncementXML	Submission_2020-09-27_23:32:59.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pierre Sabatier
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-06-18 18:11:57	ID requested
⏵ 1	2020-09-27 23:33:00	announced

Fernandez Lahore G, Raposo B, Lagerquist M, Ohlsson C, Sabatier P, Xu B, Aoun M, James J, Cai X, Zubarev RA, Nandakumar KS, Holmdahl R, Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases. Proc Natl Acad Sci U S A, 117(40):24986-24997(2020) [pubmed]

submitter keyword: inflammatory disease, T cell, vitamin D3

Roman Zubarev
contact affiliation	Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Sweden
contact email	roman.zubarev@ki.se
lab head
Pierre Sabatier
contact affiliation	Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
contact email	pierre.sabatier@ki.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019876
     1. Label: PRIDE project
     2. Name: Polymorphisms of the vitamin D receptor regulate T cells and T cell dependent inflammatory diseases