Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals

Research output: Contribution to journalArticle

Authors

  • Dimitrios Chanouzas
  • Blagoje Soskic
  • Michael F. Seldin
  • David Sansom

External organisations

  • Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, Institute of Biomedical Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
  • Centre for Rare Diseases, Institute of Translational Medicine, Birmingham Health Partners, University Hospitals Birmingham, Birmingham, UK.
  • Neuroscience and Ophthalmology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
  • Institute of Immunity and Transplantation, University College London and Royal Free Hospital
  • Department of Biochemistry and Molecular Medicine, University of California at Davis
  • Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California at Davis

Abstract

The CD28 locus is associated with susceptibility to a variety of autoimmune and immune-mediated inflammatory diseases including primary sclerosing cholangitis (PSC). Previously, we linked the CD28 pathway in PSC disease pathology and found that vitamin D could maintain CD28 expression. Here, we assessed whether the PSC-associated CD28 risk variant A (rs7426056) affects CD28 expression and T cell function in healthy individuals (n = 14 AA, n = 14 AG, n = 14 GG). Homozygotes for the PSC disease risk allele (AA) showed significantly lower CD28 mRNA expression ex-vivo than either GG or AG (p < 0.001) in total peripheral blood mononuclear cells. However, the CD28 risk variant alone was not sufficient to explain CD28 protein loss on CD4(+) T cells. All genotypes responded equally to vitamin D as indicated by induction of a regulatory phenotype and an increased anti-inflammatory/pro-inflammatory cytokine ratio. A genotypic effect on response to TNFα stimuli was detected, which was inhibited by vitamin D. Together our results show: (a) an altered gene expression in carriers of the susceptible CD28 variant, (b) no differences in protein levels on CD4(+) T cells, and

Details

Original languageEnglish
Pages (from-to)7652
JournalScientific Reports
Volume7
Issue number1
Publication statusPublished - 9 Aug 2017

Keywords

  • Journal Article