Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

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dc.contributor.authorCandia, Enzo
dc.contributor.authorReyes, Paz
dc.contributor.authorCovian, Camila
dc.contributor.authorRodriguez, Francisco
dc.contributor.authorRodriguez, Francisco
dc.contributor.authorWainstein, Nicolas
dc.contributor.authorMorales, Jorge
dc.contributor.authorMosso, Claudio
dc.contributor.authorRosemblatt, Mario
dc.contributor.authorFierro, Juan Alberto
dc.date.accessioned2024-04-13T16:23:41Z
dc.date.available2024-04-13T16:23:41Z
dc.date.issued2017-07
dc.descriptionINDEXACIÓN: SCOPUS.
dc.description.abstractAdoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells. © 2017 Candia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.identifier.citationPLoS ONE, Volume 12, Issue 7, July 2017, Article number e0182009
dc.identifier.doi10.1371/journal.pone.0182009
dc.identifier.issn1932-6203
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/55917
dc.language.isoen
dc.publisherPublic Library of Science
dc.rights.licenseCC BY 4.0 DEED Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAntineoplastic Agents
dc.subjectCells, Cultured
dc.subjectCpG Islands
dc.subjectDNA Methylation
dc.subjectDrug Synergism
dc.subjectFlow Cytometry
dc.subjectForkhead Transcription Factors
dc.subjectHumans
dc.subjectInterleukin-2
dc.subjectInterleukin-2 Receptor alpha Subunit
dc.subjectSirolimus
dc.subjectT-Lymphocytes
dc.subjectT-Lymphocytes, Regulatory
dc.subjectTransforming Growth Factor beta1
dc.subjectTretinoin
dc.subjectYoung Adult
dc.titleSingle and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells
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