title: Aurintricarboxylic acid promotes the conversion of naive CD4+CD25- T cells into Foxp3-expressing regulatory T cells.
abstract: Naive peripheral CD4(+)CD25(-) T cells can be converted into Foxp3-expressing regulatory T cells under appropriate stimulation conditions. Considering that continuous exposure to antigens is one of the prerequisites for the differentiation and maintenance of Treg cells, we investigated whether preventing activation-induced cell death while providing continuous TCR stimulation could promote the expression of Foxp3 in murine naive CD4(+) T cells. Among the several anti-apoptotic agents tested, aurintricarboxylic acid (ATA) was found to induce the in vitro conversion of naive CD4(+) T cells into Foxp3(+) Treg cells with suppressive activity. Neutralizing studies with an antibody against transforming growth factor (TGF)-β revealed that ATA requires the presence of TGF-β to induce Foxp3 expression in naive CD4(+)CD25(-) T cells. Although ATA itself did not activate the Smad signaling pathway, it down-regulated the extracellular signal-regulated kinase and mammalian target of rapamycin signaling cascade in activated T cells. Lastly, combined exposure to ATA and TGF-β had a synergistic effect on the rate of induction and maintenance of Foxp3 expression. These results indicate that ATA could be exploited to efficiently prepare inducible regulatory T cells in vitro and may aid in more precisely identifying the specific signaling pathways that drive Foxp3 expression in T cells.
authors.affiliation: Department of Surgery, Ulsan University College of Medicine and Asan Medical Center, Seoul, Korea. dglim@nmc.or.kr
authors.forename: Dong-Gyun
authors.initials: DG
authors.lastname: Lim
authors.forename: Youn-Hee
authors.initials: YH
authors.lastname: Park
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Chan-Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Song-Cheol
authors.initials: SC
authors.lastname: Kim
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
authors.forename: Duck-Jong
authors.initials: DJ
authors.lastname: Han
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D015704:CD4 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D001312:Aurintricarboxylic Acid; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases