{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T01:34:16Z","timestamp":1769045656298,"version":"3.49.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T00:00:00Z","timestamp":1605744000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"John Scott Fellowship"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier superfamily that can mediate the transfer of protons into the mitochondrial matrix from the intermembrane space. We have previously reported UCP3 expression in thymocytes, mitochondria of total splenocytes and splenic lymphocytes. Here, we demonstrate that <jats:italic>Ucp3<\/jats:italic> is expressed in peripheral naive CD4<jats:sup>+<\/jats:sup> T cells at the mRNA level before being markedly downregulated following activation. Non-polarized, activated T cells (Th0 cells) from <jats:italic>Ucp3<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice produced significantly more IL-2, had increased expression of CD25 and CD69 and were more proliferative than <jats:italic>Ucp3<\/jats:italic><jats:sup>+\/+<\/jats:sup> Th0 cells. The altered IL-2 expression observed between T cells from <jats:italic>Ucp3<\/jats:italic><jats:sup>+\/+<\/jats:sup> and <jats:italic>Ucp3<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice may be a factor in determining differentiation into Th17 or induced regulatory (iTreg) cells. When compared to <jats:italic>Ucp3<\/jats:italic><jats:sup>+\/+<\/jats:sup>, CD4<jats:sup>+<\/jats:sup> T cells from <jats:italic>Ucp3<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice had increased FoxP3 expression under iTreg conditions. Conversely, <jats:italic>Ucp3<\/jats:italic><jats:sup>-\/-<\/jats:sup> CD4<jats:sup>+<\/jats:sup> T cells produced a significantly lower concentration of IL-17A under Th17 cell-inducing conditions <jats:italic>in vitro<\/jats:italic>. These effects were mirrored in antigen-specific T cells from mice immunized with KLH and CT. Interestingly, the altered responses of <jats:italic>Ucp3<\/jats:italic><jats:sup>-\/-<\/jats:sup> T cells were partially reversed upon neutralisation of IL-2. Together, these data indicate that UCP3 acts to restrict the activation of naive T cells, acting as a rheostat to dampen signals following TCR and CD28 co-receptor ligation, thereby limiting early activation responses. The observation that <jats:italic>Ucp3<\/jats:italic> ablation alters the Th17:Treg cell balance <jats:italic>in vivo<\/jats:italic> as well as <jats:italic>in vitro<\/jats:italic> suggests that UCP3 is a potential target for the treatment of Th17 cell-mediated autoimmune diseases.<\/jats:p>","DOI":"10.1371\/journal.pone.0239713","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T19:12:45Z","timestamp":1605813165000},"page":"e0239713","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["UCP3 reciprocally controls CD4+ Th17 and Treg cell differentiation"],"prefix":"10.1371","volume":"15","author":[{"given":"Emma B.","family":"O\u2019Connor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Mu\u00f1oz-Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gemma","family":"Leon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ed C.","family":"Lavelle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kingston H. 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Lett"},{"issue":"1","key":"pone.0239713.ref005","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1006\/bbrc.1997.6740","article-title":"UCP3: An Uncoupling Protein Homologue Expressed Preferentially and Abundantly in Skeletal Muscle and Brown Adipose Tissue","volume":"235","author":"A Vidal-Puig","year":"1997","journal-title":"Biochem Biophys Res Commun"},{"issue":"3","key":"pone.0239713.ref006","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S0014-5793(98)01713-X","article-title":"UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells","volume":"443","author":"W Mao","year":"1999","journal-title":"FEBS Lett"},{"issue":"11","key":"pone.0239713.ref007","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1096\/fj.99-0834com","article-title":"Characterization of novel UCP5\/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation","volume":"14","author":"XX Yu","year":"2000","journal-title":"FASEB J"},{"key":"pone.0239713.ref008","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nrm1592","article-title":"The Mitochondrial Uncoupling-Protein Homologues","volume":"6","author":"S Krauss","year":"2005","journal-title":"Nature Rev Mol Cell Biol"},{"issue":"1","key":"pone.0239713.ref009","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbabio.2015.10.011","article-title":"The expression of UCP3 directly correlates to UCP1 abundance in brown adipose tissue","volume":"1857","author":"KE Hilse","year":"2016","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"pone.0239713.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/eje.0.1390001","article-title":"The uncoupling proteins, a review","volume":"139","author":"O Boss","year":"1998","journal-title":"Eur J 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Kelly","year":"2011","journal-title":"Biochim Biophys Acta"},{"issue":"6","key":"pone.0239713.ref020","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The Orphan Nuclear Receptor ROR\u03b3t Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells","volume":"126","author":"II Ivanov","year":"2006","journal-title":"Cell"},{"issue":"1","key":"pone.0239713.ref021","first-page":"13","article-title":"Interleukin-2 at the Crossroads of Effector Responses","volume":"38","author":"W Liao","year":"2013","journal-title":"Tolerance and Immunotherapy. 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Biol. Med"},{"key":"pone.0239713.ref037","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.plipres.2005.11.001","article-title":"Putative function and physiological relevance of the mitochondrial uncoupling protein-3:involvement in fatty acid metabolism?","volume":"45","author":"P Schrauwen","year":"2006","journal-title":"Prog. 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