{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:13:57Z","timestamp":1790828037695,"version":"4.1.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Patients infected by\n                    <jats:italic>Leishmania braziliensis<\/jats:italic>\n                    develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell subsets. Moreover, PDL-1\/PDL-2 ligands were increased on skin macrophages compared to healthy controls. The proportions PD1\n                    <jats:sup>+<\/jats:sup>\n                    , but not TIM-3 or CTLA-4 expressing T cells in the circulation were positively correlated with those in the lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative capacity and IFN-\u03b3 production, but not TNF-\u03b1 secretion in response to\n                    <jats:italic>L. braziliensis<\/jats:italic>\n                    recall antigen challenge\n                    <jats:italic>in vitro<\/jats:italic>\n                    . While we previously showed a significant correlation between the accumulation of senescent CD8\n                    <jats:sup>+<\/jats:sup>\n                    CD45RA\n                    <jats:sup>+<\/jats:sup>\n                    CD27\n                    <jats:sup>-<\/jats:sup>\n                    T cells in the circulation and skin lesion size in the patients, there was no such correlation between the extent of PD-1 expression by circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells may not contribute to the cutaneous immunopathology. Nevertheless, we identified exhausted-like T cells in both skin lesions and in the blood. Targeting this population by PD-1 blockade may improve T cell function and thus accelerate parasite clearance that would reduce the cutaneous pathology in cutaneous leishmaniasis.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2021.632667","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:19:27Z","timestamp":1615249167000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis"],"prefix":"10.3389","volume":"12","author":[{"given":"Renan","family":"Garcia de Moura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana Polaco","family":"Covre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Henrique","family":"Fantecelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitor Alejandro Torres","family":"Gajardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla Baroni","family":"Cunha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzzo Lyrio","family":"Stringari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashton Trey","family":"Belew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila Batista","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra Ventorin Von","family":"Zeidler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Eduardo","family":"Tadokoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert Leonel","family":"de Matos Guedes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael Lubiana","family":"Zanotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mosser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aloisio","family":"Falqueto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne N.","family":"Akbar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Claudio Oliveira","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"B1","article-title":"OMS | Leishmaniasis","volume-title":"WHO","year":"2015"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02083-14","article-title":"Comparative Evaluation of Lesion Development, Tissue Damage, and Cytokine Expression in Golden Hamsters (Mesocricetus auratus) Infected by Inocula with Different Leishmania (Viannia) braziliensis Concentrations","volume":"82","author":"Ribeiro-Romao","year":"2014","journal-title":"Infect Immun"},{"key":"B3","first-page":"70","article-title":"Clinical modalities, diagnosis and therapeutic approach of tegumentary leishmaniasis in Brazil","volume":"143","author":"Costa","year":"2009","journal-title":"Gaz Med Da Bahia"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00301","article-title":"Protective and pathologic immune responses in human tegumentary leishmaniasis","volume":"3","author":"Carvalho","year":"2012","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.72","article-title":"Cutaneous leishmaniasis: immune responses in protection and pathogenesis","volume":"16","author":"Scott","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3024.2009.01125.x","article-title":"Recruitment of CD8(+) T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis","volume":"31","author":"Faria","year":"2009","journal-title":"Parasite Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.12.6734-6740.2002","article-title":"Up-regulation of Th1-type responses in mucosal leishmaniasis patients","volume":"70","author":"Bacellar","year":"2002","journal-title":"Infect Immun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.12.7853-7859.2005","article-title":"Decreased in situ expression of interleukin-10 receptor is correlated with the exacerbated inflammatory and cytotoxic responses observed in mucosal leishmaniasis","volume":"73","author":"Faria","year":"2005","journal-title":"Infect Immun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00310","article-title":"Inhibitory receptors beyond T cell exhaustion","volume":"6","author":"Fuertes Marraco","year":"2015","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2010.03255.x","article-title":"Cox M a, Zajac AJ. T-cell exhaustion: characteristics, causes and conversion","volume":"129","author":"Yi","year":"2010","journal-title":"Immunology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2016.03.007","article-title":"PD-1 function in apoptosis of T lymphocytes in canine visceral leishmaniasis","volume":"221","author":"Chiku","year":"2016","journal-title":"Immunobiology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit401","article-title":"CD8 T cell exhaustion in human visceral leishmaniasis","volume":"209","author":"Gautam","year":"2014","journal-title":"J Infect Dis"},{"key":"B14","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.cimid.2018.12.002","article-title":"PD-1 and PD-L1 regulate cellular immunity in canine visceral leishmaniasis","volume":"62","author":"Oliveira Silva","year":"2019","journal-title":"Comp Immunol Microbiol Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e00019","DOI":"10.1128\/IAI.00019-18","article-title":"PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of Leishmania donovani","volume":"86","author":"Habib","year":"2018","journal-title":"Infect Immun"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00393","article-title":"Phenotypic and Functional Profiles of Antigen-Specific CD4+ and CD8+ T Cells Associated With Infection Control in Patients With Cutaneous Leishmaniasis","volume":"8","author":"Egui","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-019-56336-8","article-title":"Immunotherapy using anti-PD-1 and anti-PD-L1 in Leishmania amazonensis-infected BALB\/c mice reduce parasite load","volume":"9","author":"da Fonseca-Martins","year":"2019","journal-title":"Sci Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301810","article-title":"Programmed Death 1-Mediated T Cell Exhaustion during Visceral Leishmaniasis Impairs Phagocyte Function","volume":"191","author":"Esch","year":"2013","journal-title":"J Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e871","DOI":"10.1371\/journal.pntd.0000871","article-title":"CD8 cells of patients with diffuse cutaneous leishmaniasis display functional exhaustion: The latter is reversed, in vitro, by TLR2 agonists","volume":"4","author":"Hern\u00e1ndez-Ruiz","year":"2010","journal-title":"PloS Negl Trop Dis"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-37144-y","article-title":"Impaired activation of lesional CD8+ T-cells is associated with enhanced expression of Programmed Death-1 in Indian Post Kala-azar Dermal Leishmaniasis","volume":"9","author":"Mukherjee","year":"2019","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-08798-7","article-title":"PD-1 blockade potentiates HIV latency reversal ex vivo in CD4 + T cells from ART-suppressed individuals","volume":"814","author":"Fromentin","year":"2019","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2011.03550.x","article-title":"Reversal of functional defects in highly differentiated young and old CD8 T cells by PDL blockade","volume":"135","author":"Henson","year":"2012","journal-title":"Immunology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201445312","article-title":"Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8+ T-cell proliferation by distinct pathways","volume":"45","author":"Henson","year":"2015","journal-title":"Eur J Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/JVI.01263-17","article-title":"Differential Inhibitory Receptor Expression on T Cells Delineates Functional Capacities in Chronic Viral Infection","volume":"91","author":"Teigler","year":"2017","journal-title":"J Virol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2017.01.028","article-title":"Anti-PD-1\/PD-L1 therapy for infectious diseases: learning from the cancer paradigm","volume":"56","author":"Rao","year":"2017","journal-title":"Int J Infect Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202537.Parasite-derived","article-title":"Parasite-derived arginase influences secondary anti-Leishmania immunity by regulating PD-1-mediated CD4+ T cell exhaustion","volume":"190","author":"Mou","year":"2013","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e1000431","DOI":"10.1371\/journal.ppat.1000431","article-title":"B7-H1 blockade increases survival of dysfunctional CD8+ T cells and confers protection against Leishmania donovaniinfections","volume":"5","author":"Joshi","year":"2009","journal-title":"PloS Pathog"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pntd.0004992","article-title":"Meta-transcriptome Profiling of the Human-Leishmania braziliensis Cutaneous Lesion","volume":"10","author":"Christensen","year":"2016","journal-title":"PloS Negl Trop Dis"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"Wickham","year":"2016"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13173","article-title":"Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8+ T cells in human cutaneous leishmaniasis","volume":"159","author":"Covre","year":"2020","journal-title":"Immunology"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03001","article-title":"Circulating senescent T cells are linked to systemic inflammation and lesion size during human cutaneous leishmaniasis","volume":"10","author":"Covre","year":"2019","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01021","article-title":"PD-L1 May Mediate T-Cell Exhaustion in a Case of Early Diffuse Leishmaniasis Caused by Leishmania (L.) amazonensis","volume":"9","author":"Barroso","year":"2018","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00455","article-title":"Inhibitory receptor expression depends more dominantly on differentiation and activation than \u201cexhaustion\u201d of human CD8 T cells","volume":"4","author":"Legat","year":"2013","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.09.006","article-title":"Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection","volume":"27","author":"Wherry","year":"2007","journal-title":"Immunity"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0b013e32834ddcf2","article-title":"Acquired transcriptional programming in functional and exhausted virus-specific CD8 T cells","volume":"7","author":"Youngblood","year":"2012","journal-title":"Curr Opin HIV AIDS"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e40146","DOI":"10.1371\/journal.pone.0040146","article-title":"Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection","volume":"7","author":"Sakhdari","year":"2012","journal-title":"PloS One"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2013.4","article-title":"CD8+ Granzyme B+\u2013Mediated Tissue Injury vs. CD4+IFN\u03b3+\u2013Mediated Parasite Killing in Human Cutaneous Leishmaniasis","volume":"133","author":"Santos C da","year":"2013","journal-title":"J\u00a0Invest Dermatol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1128\/IAI.02404-14","article-title":"Protective and pathological functions of CD8+ T cells in Leishmania braziliensis infection","volume":"83","author":"Cardoso","year":"2015","journal-title":"Infect Immun"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jid.2019.05.025","article-title":"Glyburide, a NLRP3 Inhibitor, Decreases Inflammatory Response and Is a Candidate to Reduce Pathology in Leishmania braziliensis Infection","volume":"140","author":"Carvalho","year":"2019","journal-title":"J\u00a0Invest Dermatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2015.07.020","article-title":"The pentavalent antimonial therapy against experimental Leishmania amazonensis infection is more effective under the inhibition of the NF-\u03baB pathway","volume":"28","author":"Macedo","year":"2015","journal-title":"Int Immunopharmacol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.632667\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:19:33Z","timestamp":1615249173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.632667\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,9]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2021.632667"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.632667","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,9]]},"article-number":"632667"}}