{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:10:42Z","timestamp":1791223842742,"version":"4.1.0"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Public Health Service","award":["1U01AI131285"],"award-info":[{"award-number":["1U01AI131285"]}]},{"name":"Public Health Service","award":["UM1AI164556"],"award-info":[{"award-number":["UM1AI164556"]}]},{"name":"University of Pittsburgh School of Medicine"},{"name":"Public Health Service","award":["AI138504"],"award-info":[{"award-number":["AI138504"]}]},{"name":"Public Health Service","award":["CA206517"],"award-info":[{"award-number":["CA206517"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>TIM-3 expression is increased on peripheral regulatory T cells (Tregs) of virally suppressed persons with HIV-1 on antiretroviral therapy (PWH-ART). However, the relevance of TIM-3 expression in this setting is unclear. We used flow cytometry to evaluate the suppressive phenotype and signaling pathways in peripheral TIM-3\u2212 vs TIM-3+ Tregs in PWH-ART. TIM-3+ Tregs showed increased expression of IL-10 compared with persons without HIV-1. In addition, TIM-3+ Tregs displayed elevated signaling and activation, relative to TIM-3\u2212 Tregs from the same PWH-ART. Dramatically, TIM-3 blockade restrained the in vitro suppressive capacity of peripheral Tregs. Therefore, our data demonstrate not only that TIM-3 expression by Tregs is associated with an immunosuppressive response among PWH-ART, but also that TIM-3 contributes directly to the enhanced suppressive activity of Tregs in this setting.<\/jats:p>","DOI":"10.1093\/jleuko\/qiad068","type":"journal-article","created":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T12:08:14Z","timestamp":1687522094000},"page":"368-372","source":"Crossref","is-referenced-by-count":5,"title":["TIM-3 signaling contributes to the suppressive capacity of Tregs from people with HIV on antiretroviral therapy"],"prefix":"10.1093","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8084-0728","authenticated-orcid":false,"given":"Hector M","family":"Nieves-Rosado","sequence":"first","affiliation":[{"name":"Program in Microbiology and Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15261 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana L","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma","family":"Naqvi","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W","family":"Mellors","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard J C","family":"Macatangay","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence P","family":"Kane","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15261 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"issue":"6","key":"2023092800550568900_qiad068-B1","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1073\/pnas.1015148108","article-title":"Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8+ T cells and reduces chronic retroviral set points","volume":"108","author":"Dietze","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2023092800550568900_qiad068-B2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1128\/JVI.01768-07","article-title":"Natural regulatory T cells and persistent viral infection","volume":"82","author":"Li","year":"2008","journal-title":"J Virol"},{"issue":"10","key":"2023092800550568900_qiad068-B3","doi-asserted-by":"crossref","first-page":"e3305","DOI":"10.1371\/journal.pone.0003305","article-title":"Resting regulatory CD4 T cells: a site of HIV persistence in patients on long-term effective antiretroviral therapy","volume":"3","author":"Tran","year":"2008","journal-title":"PLoS One"},{"key":"2023092800550568900_qiad068-B4","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.virusres.2017.07.008","article-title":"Assessment of the HIV-1 reservoir in CD4+ regulatory T cells by a droplet digital PCR based approach","volume":"240","author":"Dunay","year":"2017","journal-title":"Virus Res"},{"issue":"3","key":"2023092800550568900_qiad068-B5","doi-asserted-by":"crossref","first-page":"e58006","DOI":"10.1371\/journal.pone.0058006","article-title":"Tim-3 expression defines regulatory T cells in human tumors","volume":"8","author":"Yan","year":"2013","journal-title":"PLoS One"},{"issue":"2","key":"2023092800550568900_qiad068-B6","doi-asserted-by":"crossref","first-page":"755","DOI":"10.4049\/jimmunol.1200162","article-title":"Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection","volume":"189","author":"Moorman","year":"2012","journal-title":"J Immunol"},{"issue":"2","key":"2023092800550568900_qiad068-B7","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1002\/eji.201242768","article-title":"HCV-infected hepatocytes drive CD4+ CD25+ Foxp3+ regulatory T-cell development through the Tim-3\/Gal-9 pathway","volume":"43","author":"Ji","year":"2013","journal-title":"Eur J Immunol"},{"issue":"5","key":"2023092800550568900_qiad068-B8","doi-asserted-by":"crossref","first-page":"e1289","DOI":"10.1002\/cti2.1289","article-title":"Differential transcriptional and functional properties of regulatory T cells in HIV-infected individuals on antiretroviral therapy and long-term non-progressors","volume":"10","author":"Shahbaz","year":"2021","journal-title":"Clin Transl Immunology"},{"key":"2023092800550568900_qiad068-B9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-1-61737-979-6_2","article-title":"In vitro Treg suppression assays","volume":"707","author":"Collison","year":"2011","journal-title":"Methods Mol Biol"},{"issue":"2","key":"2023092800550568900_qiad068-B10","doi-asserted-by":"crossref","first-page":"e1385690","DOI":"10.1080\/2162402X.2017.1385690","article-title":"Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy","volume":"7","author":"Sabatos-Peyton","year":"2018","journal-title":"Oncoimmunology"},{"issue":"1","key":"2023092800550568900_qiad068-B11","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12981-022-00465-0","article-title":"Identification of CD8+ T cell subsets that normalize in early-treated people living with HIV receiving antiretroviral therapy","volume":"19","author":"Perdomo-Celis","year":"2022","journal-title":"AIDS Res Ther"},{"issue":"12","key":"2023092800550568900_qiad068-B12","doi-asserted-by":"crossref","first-page":"4707","DOI":"10.1182\/blood-2004-04-1407","article-title":"Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo","volume":"105","author":"Erdmann","year":"2005","journal-title":"Blood"},{"issue":"9","key":"2023092800550568900_qiad068-B13","doi-asserted-by":"crossref","first-page":"ofab396","DOI":"10.1093\/ofid\/ofab396","article-title":"The adenosine pathway and human immunodeficiency virus-associated inflammation","volume":"8","author":"Hixson","year":"2021","journal-title":"Open Forum Infect Dis"},{"issue":"12","key":"2023092800550568900_qiad068-B14","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1038\/ni.3868","article-title":"Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor","volume":"18","author":"Maj","year":"2017","journal-title":"Nat Immunol"},{"issue":"8","key":"2023092800550568900_qiad068-B15","doi-asserted-by":"crossref","first-page":"3665","DOI":"10.4049\/jimmunol.1402898","article-title":"IL-10 potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1","volume":"195","author":"Hsu","year":"2015","journal-title":"J Immunol"},{"issue":"1","key":"2023092800550568900_qiad068-B16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1046\/j.1365-2249.1999.00865.x","article-title":"IL-10 in HIV infection: increasing serum IL-10 levels with disease progression\u2013down-regulatory effect of potent anti-retroviral therapy","volume":"116","author":"Stylianou","year":"1999","journal-title":"Clin Exp Immunol"},{"issue":"7","key":"2023092800550568900_qiad068-B17","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1172\/JCI45138","article-title":"Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs","volume":"122","author":"Gupta","year":"2012","journal-title":"J Clin Invest"},{"issue":"3","key":"2023092800550568900_qiad068-B18","doi-asserted-by":"crossref","first-page":"101042","DOI":"10.1016\/j.jbc.2021.101042","article-title":"The HIV-1 accessory protein Nef increases surface expression of the checkpoint receptor Tim-3 in infected CD4+ T cells","volume":"297","author":"Jacob","year":"2021","journal-title":"J Biol Chem"},{"issue":"10","key":"2023092800550568900_qiad068-B19","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1073\/pnas.1712107115","article-title":"Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion","volume":"115","author":"Avery","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"19","key":"2023092800550568900_qiad068-B20","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1128\/MCB.05297-11","article-title":"Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways","volume":"31","author":"Lee","year":"2011","journal-title":"Mol Cell Biol"},{"issue":"11","key":"2023092800550568900_qiad068-B21","doi-asserted-by":"crossref","first-page":"109699","DOI":"10.1016\/j.celrep.2021.109699","article-title":"Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment","volume":"36","author":"Banerjee","year":"2021","journal-title":"Cell Rep"},{"issue":"18","key":"2023092800550568900_qiad068-B22","doi-asserted-by":"crossref","first-page":"4529","DOI":"10.1158\/1078-0432.CCR-17-1350","article-title":"Novel effector phenotype of Tim-3(+) regulatory T cells leads to enhanced suppressive function in head and neck cancer patients","volume":"24","author":"Liu","year":"2018","journal-title":"Clin Cancer Res"}],"container-title":["Journal of Leukocyte Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jleukbio\/advance-article-pdf\/doi\/10.1093\/jleuko\/qiad068\/50890038\/qiad068.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/114\/4\/368\/51780556\/qiad068.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/114\/4\/368\/51780556\/qiad068.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T00:55:30Z","timestamp":1695862530000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jleukbio\/article\/114\/4\/368\/7205611"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,23]]},"references-count":22,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,6,23]]},"published-print":{"date-parts":[[2023,9,27]]}},"URL":"https:\/\/doi.org\/10.1093\/jleuko\/qiad068","relation":{},"ISSN":["1938-3673"],"issn-type":[{"value":"1938-3673","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,10]]},"published":{"date-parts":[[2023,6,23]]}}}