Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells
Adoptive 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...
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| Veröffentlicht in: | PloS one 2017-07, Vol.12 (7), p.e0182009-e0182009 |
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| creator | Candia, Enzo Reyes, Paz Covian, Camila Rodriguez, Francisco Wainstein, Nicolas Morales, Jorge Mosso, Claudio Rosemblatt, Mario Fierro, Juan Alberto |
| description | Adoptive 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. |
| doi_str_mv | 10.1371/journal.pone.0182009 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0182009</identifier><identifier>PMID: 28746369</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Adolescent ; Adoptive transfer ; Adult ; Antigens ; Antineoplastic Agents - pharmacology ; Assaying ; Autoimmune diseases ; Biology and life sciences ; CD25 antigen ; CD4 antigen ; Cell culture ; Cell proliferation ; Cells, Cultured ; Conserved sequence ; CpG Islands - genetics ; CXCR4 protein ; Cytokines ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA Methylation - drug effects ; Drug Synergism ; Effector cells ; Epigenetics ; Flow Cytometry ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - immunology ; Forkhead Transcription Factors - metabolism ; Foxp3 protein ; Gene expression ; Graft rejection ; Graft-versus-host reaction ; Homing ; Human performance ; Humans ; Immunoregulation ; In vitro methods and tests ; Interleukin 2 ; Interleukin-2 - pharmacology ; Interleukin-2 Receptor alpha Subunit - genetics ; Interleukin-2 Receptor alpha Subunit - immunology ; Interleukin-2 Receptor alpha Subunit - metabolism ; Lymphocytes ; Lymphocytes T ; Markers ; Medicine and health sciences ; Physical Sciences ; Rapamycin ; Rejection ; Research and Analysis Methods ; Retinoic acid ; Sirolimus - pharmacology ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - metabolism ; Transforming Growth Factor beta1 - pharmacology ; Transforming growth factor-b1 ; Transplants & implants ; Tretinoin - pharmacology ; Young Adult</subject><ispartof>PloS one, 2017-07, Vol.12 (7), p.e0182009-e0182009</ispartof><rights>2017 Candia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Candia et al 2017 Candia et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-a82a4a5c041550dcb85e4e9ff45b87d35014c37b4bb8b34a825afadebea2d48b3</citedby><cites>FETCH-LOGICAL-c526t-a82a4a5c041550dcb85e4e9ff45b87d35014c37b4bb8b34a825afadebea2d48b3</cites><orcidid>0000-0001-7081-5860</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529012/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529012/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28746369$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Boussiotis, Vassiliki A.</contributor><creatorcontrib>Candia, Enzo</creatorcontrib><creatorcontrib>Reyes, Paz</creatorcontrib><creatorcontrib>Covian, Camila</creatorcontrib><creatorcontrib>Rodriguez, Francisco</creatorcontrib><creatorcontrib>Wainstein, Nicolas</creatorcontrib><creatorcontrib>Morales, Jorge</creatorcontrib><creatorcontrib>Mosso, Claudio</creatorcontrib><creatorcontrib>Rosemblatt, Mario</creatorcontrib><creatorcontrib>Fierro, Juan Alberto</creatorcontrib><title>Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Adoptive 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.</description><subject>Acids</subject><subject>Adolescent</subject><subject>Adoptive transfer</subject><subject>Adult</subject><subject>Antigens</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Assaying</subject><subject>Autoimmune diseases</subject><subject>Biology and life sciences</subject><subject>CD25 antigen</subject><subject>CD4 antigen</subject><subject>Cell culture</subject><subject>Cell proliferation</subject><subject>Cells, Cultured</subject><subject>Conserved sequence</subject><subject>CpG Islands - genetics</subject><subject>CXCR4 protein</subject><subject>Cytokines</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - drug effects</subject><subject>Drug Synergism</subject><subject>Effector cells</subject><subject>Epigenetics</subject><subject>Flow Cytometry</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - immunology</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Foxp3 protein</subject><subject>Gene expression</subject><subject>Graft rejection</subject><subject>Graft-versus-host reaction</subject><subject>Homing</subject><subject>Human performance</subject><subject>Humans</subject><subject>Immunoregulation</subject><subject>In vitro methods and tests</subject><subject>Interleukin 2</subject><subject>Interleukin-2 - pharmacology</subject><subject>Interleukin-2 Receptor alpha Subunit - genetics</subject><subject>Interleukin-2 Receptor alpha Subunit - immunology</subject><subject>Interleukin-2 Receptor alpha Subunit - metabolism</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Markers</subject><subject>Medicine and health sciences</subject><subject>Physical Sciences</subject><subject>Rapamycin</subject><subject>Rejection</subject><subject>Research and Analysis Methods</subject><subject>Retinoic acid</subject><subject>Sirolimus - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Candia, Enzo</au><au>Reyes, Paz</au><au>Covian, Camila</au><au>Rodriguez, Francisco</au><au>Wainstein, Nicolas</au><au>Morales, Jorge</au><au>Mosso, Claudio</au><au>Rosemblatt, Mario</au><au>Fierro, Juan Alberto</au><au>Boussiotis, Vassiliki A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-07-26</date><risdate>2017</risdate><volume>12</volume><issue>7</issue><spage>e0182009</spage><epage>e0182009</epage><pages>e0182009-e0182009</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Adoptive 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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28746369</pmid><doi>10.1371/journal.pone.0182009</doi><orcidid>https://orcid.org/0000-0001-7081-5860</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-07, Vol.12 (7), p.e0182009-e0182009 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1923717875 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acids Adolescent Adoptive transfer Adult Antigens Antineoplastic Agents - pharmacology Assaying Autoimmune diseases Biology and life sciences CD25 antigen CD4 antigen Cell culture Cell proliferation Cells, Cultured Conserved sequence CpG Islands - genetics CXCR4 protein Cytokines Deoxyribonucleic acid DNA DNA methylation DNA Methylation - drug effects Drug Synergism Effector cells Epigenetics Flow Cytometry Forkhead Transcription Factors - genetics Forkhead Transcription Factors - immunology Forkhead Transcription Factors - metabolism Foxp3 protein Gene expression Graft rejection Graft-versus-host reaction Homing Human performance Humans Immunoregulation In vitro methods and tests Interleukin 2 Interleukin-2 - pharmacology Interleukin-2 Receptor alpha Subunit - genetics Interleukin-2 Receptor alpha Subunit - immunology Interleukin-2 Receptor alpha Subunit - metabolism Lymphocytes Lymphocytes T Markers Medicine and health sciences Physical Sciences Rapamycin Rejection Research and Analysis Methods Retinoic acid Sirolimus - pharmacology T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism Transforming Growth Factor beta1 - pharmacology Transforming growth factor-b1 Transplants & implants Tretinoin - pharmacology Young Adult |
| title | 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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