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Lymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivo

2015Journal article Open access
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dc.contributor.authorCosta, M.
dc.contributor.authorCruz, E.
dc.contributor.authorOliveira, S.
dc.contributor.authorBenes, Vl.
dc.contributor.authorIvacevic, T.
dc.contributor.authorSilva, M.
dc.contributor.authorVieira, I.
dc.contributor.authorDias, F.
dc.contributor.authorFonseca, S.
dc.contributor.authorGonçalves, M.
dc.contributor.authorLima, M.
dc.contributor.authorLeitão, C.
dc.contributor.authorMuckenthaler, M.
dc.contributor.authorPinto, J.
dc.contributor.authorPorto, G.
dc.date.accessioned2016-05-02T09:47:09Z
dc.date.available2016-05-02T09:47:09Z
dc.date.issued2015
dc.description.abstractAbnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe-/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe-/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH.pt_PT
dc.identifier.citationPLoS One. 2015;10(4):e012424pt_PT
dc.identifier.doi10.1371/journal.pone.0124246pt_PT
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.16/1934
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPublic Library of Sciencept_PT
dc.relationFCOMP-01-0124-FEDER-015823 (PTDC/SAU/MET/113011/2009)pt_PT
dc.relationMODIFIERS OF EXPRESSION OF HEMOCHROMATOSIS: looking for new markers of disease prognosis
dc.relationINOVA/APRF, USA grantpt_PT
dc.relationLYMPHOCYTES IN HEMOCHROMATOSIS: A GENOMIC AND FUNCTIONAL APPROACH
dc.relation.publisherversionhttp://journals.plos.org/plosone/article/asset?id=10.1371%2Fjournal.pone.0124246.PDFpt_PT
dc.titleLymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivopt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMODIFIERS OF EXPRESSION OF HEMOCHROMATOSIS: looking for new markers of disease prognosis
oaire.awardTitleLYMPHOCYTES IN HEMOCHROMATOSIS: A GENOMIC AND FUNCTIONAL APPROACH
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PIC%2FIC%2F82785%2F2007/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F69186%2F2010/PT
oaire.citation.conferencePlaceUnited States of Americapt_PT
oaire.citation.issue4pt_PT
oaire.citation.startPagee012424pt_PT
oaire.citation.titlePlos onept_PT
oaire.citation.volume10pt_PT
oaire.fundingStream5876-PPCDTI
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication2acf6ee6-a9cd-45a9-9a1f-b6813c5f0ecd
relation.isProjectOfPublicationef8c6a9a-6730-4593-aa54-821466af57a1
relation.isProjectOfPublication.latestForDiscoveryef8c6a9a-6730-4593-aa54-821466af57a1

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