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

Evaggelia Liaskou, Louisa Jeffery, Dimitrios Chanouzas, Blagoje Soskic, Michael F Seldin, Lorraine Harper, David Sansom, Gideon M. Hirschfield

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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 (c) a protective effect of the variant upon CD28 protein loss on CD4+ T cells under inflammatory conditions.

Original languageEnglish (US)
Article number7652
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Sclerosing Cholangitis
Vitamin D
T-Lymphocytes
Proteins
Homozygote
Blood Cells
Anti-Inflammatory Agents
Alleles
Genotype
Pathology
Cytokines
Phenotype
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • General

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Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals. / Liaskou, Evaggelia; Jeffery, Louisa; Chanouzas, Dimitrios; Soskic, Blagoje; Seldin, Michael F; Harper, Lorraine; Sansom, David; Hirschfield, Gideon M.

In: Scientific Reports, Vol. 7, No. 1, 7652, 01.12.2017.

Research output: Contribution to journalArticle

Liaskou, Evaggelia ; Jeffery, Louisa ; Chanouzas, Dimitrios ; Soskic, Blagoje ; Seldin, Michael F ; Harper, Lorraine ; Sansom, David ; Hirschfield, Gideon M. / Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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