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Two Separate Effects Contribute to Regulatory T Cell Defect in Systemic Lupus Erythematosus Patients and Their Unaffected Relatives

dc.contributor.authorCosta, N
dc.contributor.authorMarques, O
dc.contributor.authorGodinho, SI
dc.contributor.authorCarvalho, C
dc.contributor.authorLeal, B
dc.contributor.authorFigueiredo, AM
dc.contributor.authorVasconcelos, C
dc.contributor.authorMarinho, A
dc.contributor.authorMoraes-Fontes, MF
dc.contributor.authorGomes da Costa, A
dc.contributor.authorPonte, C
dc.contributor.authorCampanilho-Marques, R
dc.contributor.authorCóias, T
dc.contributor.authorMartins, AR
dc.contributor.authorViana, JF
dc.contributor.authorLima, M
dc.contributor.authorMartins, B
dc.contributor.authorFesel, C
dc.date.accessioned2018-01-31T15:32:38Z
dc.date.available2018-01-31T15:32:38Z
dc.date.issued2017-09
dc.description.abstractForkhead box P3 (FoxP3)+ regulatory T cells (Tregs ) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg ) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+ FoxP3+ CD45RO- CD31+ recent thymic emigrant Tregs . This first component effect influenced the proportions of circulating CD4+ FoxP3high CD45RO+ activated Tregs . (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs , SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs , but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg -directed therapies can be monitored more effectively when taking this distinction into account.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationClin Exp Immunol. 2017 Sep;189(3):318-330pt_PT
dc.identifier.doi10.1111/cei.12991pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.17/2872
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherJohn Wiley and Sonspt_PT
dc.subjectAdultpt_PT
dc.subjectAgedpt_PT
dc.subjectFemalept_PT
dc.subjectFlow Cytometrypt_PT
dc.subjectHumanspt_PT
dc.subjectInterleukin-2pt_PT
dc.subjectInterleukin-2 Receptor alpha Subunitpt_PT
dc.subjectLeukocyte Common Antigenspt_PT
dc.subjectLupus Erythematosus, Systemicpt_PT
dc.subjectLymphocyte Activationpt_PT
dc.subjectMalept_PT
dc.subjectMiddle Agedpt_PT
dc.subjectPhenotypept_PT
dc.subjectT-Lymphocytes, Regulatorypt_PT
dc.subjectUp-Regulationpt_PT
dc.subjectYoung Adultpt_PT
dc.subjectFamilypt_PT
dc.subjectHCC MEDpt_PT
dc.titleTwo Separate Effects Contribute to Regulatory T Cell Defect in Systemic Lupus Erythematosus Patients and Their Unaffected Relativespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage330pt_PT
oaire.citation.issue3pt_PT
oaire.citation.startPage318pt_PT
oaire.citation.titleClinical and Experimental Immunologypt_PT
oaire.citation.volume189pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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