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

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...

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Autores principales:	Evaggelia Liaskou, Louisa Jeffery, Dimitrios Chanouzas, Blagoje Soskic, Michael F. Seldin, Lorraine Harper, David Sansom, Gideon M. Hirschfield
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e5a9b051286947d2a6faeaf9453b110f
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spelling	oai:doaj.org-article:e5a9b051286947d2a6faeaf9453b110f2021-12-02T15:05:12ZGenetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals10.1038/s41598-017-07967-22045-2322https://doaj.org/article/e5a9b051286947d2a6faeaf9453b110f2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07967-2https://doaj.org/toc/2045-2322Abstract 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.Evaggelia LiaskouLouisa JefferyDimitrios ChanouzasBlagoje SoskicMichael F. SeldinLorraine HarperDavid SansomGideon M. HirschfieldNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Evaggelia Liaskou Louisa Jeffery Dimitrios Chanouzas Blagoje Soskic Michael F. Seldin Lorraine Harper David Sansom Gideon M. Hirschfield Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals
description	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.
format	article
author	Evaggelia Liaskou Louisa Jeffery Dimitrios Chanouzas Blagoje Soskic Michael F. Seldin Lorraine Harper David Sansom Gideon M. Hirschfield
author_facet	Evaggelia Liaskou Louisa Jeffery Dimitrios Chanouzas Blagoje Soskic Michael F. Seldin Lorraine Harper David Sansom Gideon M. Hirschfield
author_sort	Evaggelia Liaskou
title	Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals
title_short	Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals
title_full	Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals
title_fullStr	Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals
title_full_unstemmed	Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals
title_sort	genetic variation at the cd28 locus and its impact on expansion of pro-inflammatory cd28 negative t cells in healthy individuals
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e5a9b051286947d2a6faeaf9453b110f
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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

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