{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T04:10:20Z","timestamp":1794370220552,"version":"4.9.0"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T00:00:00Z","timestamp":1577664000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T00:00:00Z","timestamp":1577664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Leishmaniasis is a neglected disease, for which current treatment presents numerous issues.<jats:italic>Leishmania amazonensis<\/jats:italic>is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The roles of the programmed death-1 (PD-1) receptor on lymphocytes and its ligand (PD-L1) on antigen-presenting cells have been well studied in tumor and other infection models; but little is known about their roles in non-healing cutaneous leishmaniasis. In this study, we observed that<jats:italic>L. amazonensis<\/jats:italic>induced PD-1 expression on both CD4<jats:sup>+<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>T cells and PD-L1 on dendritic cells on BALB\/c mice. We tested the therapeutic potential of anti-PD-1 and anti-PD-L1 monoclonal antibodies (MoAbs) against a non-healing<jats:italic>L. amazonensis<\/jats:italic>infection in BALB\/c mice, and that anti-PD-1 and anti-PD-L1 treatment significantly increased IFN-\u03b3-producing CD4<jats:sup>+<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>T cells, respectively. Compared with infection controls, mice treated with anti-PD-1 and anti-PD-L1, but not anti-PD-L2, displayed bigger lesions with significantly lower parasite loads. Treatment did not affect anti-<jats:italic>Leishmania<\/jats:italic>antibody (IgM, IgG, IgG1 and IgG2a) or IL-10 production, but anti-PD-1 treatment reduced both IL-4 and TGF-\u03b2 production. Together, our results highlight the therapeutic potential of an anti-PD-1-based treatment in promoting the reinvigoration of T cells for the control of parasite burden.<\/jats:p>","DOI":"10.1038\/s41598-019-56336-8","type":"journal-article","created":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T11:02:44Z","timestamp":1577703764000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Immunotherapy using anti-PD-1 and anti-PD-L1 in Leishmania amazonensis-infected BALB\/c mice reduce parasite load"],"prefix":"10.1038","volume":"9","author":[{"given":"Alessandra M.","family":"da Fonseca-Martins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8523-4361","authenticated-orcid":false,"given":"Tadeu D.","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana E. S.","family":"Pratti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8971-8163","authenticated-orcid":false,"given":"Luan","family":"Firmino-Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Claudio Oliveira","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Soong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira M.","family":"Saraiva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-3069","authenticated-orcid":false,"given":"Herbert L.","family":"de Matos Guedes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,30]]},"reference":[{"issue":"11","key":"56336_CR1","doi-asserted-by":"publisher","first-page":"3887","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","volume":"11","author":"Y Ishida","year":"1992","unstructured":"Ishida, Y., Agata, Y., Shibahara, K. & Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. The EMBO journal 11(11), 3887\u20133895 (1992).","journal-title":"The EMBO journal"},{"key":"56336_CR2","doi-asserted-by":"publisher","first-page":"750","DOI":"10.12688\/f1000research.11120.1","volume":"6","author":"E Torres-Guerrero","year":"2017","unstructured":"Torres-Guerrero, E., Quintanilla-Cedillo, M. R., Ruiz-Esmenjaud, J. & Arenas, R. Leishmaniasis: a review. F1000Research 6, 750, https:\/\/doi.org\/10.12688\/f1000research.11120.1 (2017).","journal-title":"F1000Research"},{"key":"56336_CR3","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1038\/70932","volume":"5","author":"H Dong","year":"1999","unstructured":"Dong, H. et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5, 1365\u20131369, https:\/\/doi.org\/10.1038\/70932 (1999).","journal-title":"Nat Med"},{"key":"56336_CR4","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/S1471-4906(01)01888-9","volume":"22","author":"H Nishimura","year":"2001","unstructured":"Nishimura, H. & Honjo, T. PD-1: An inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 22, 265\u2013268, https:\/\/doi.org\/10.1016\/S1471-4906(01)01888-9 (2001).","journal-title":"Trends Immunol."},{"issue":"9","key":"56336_CR5","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1093\/intimm\/dxp072","volume":"21","author":"W Wang","year":"2009","unstructured":"Wang, W. et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4\u2009+\u2009CD25(Hi) regulatory T cells. International immunology 21(9), 1065\u20131077, https:\/\/doi.org\/10.1093\/intimm\/dxp072 (2009).","journal-title":"International immunology"},{"issue":"5","key":"56336_CR6","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1093\/humupd\/dmp004","volume":"15","author":"LR Guerin","year":"2009","unstructured":"Guerin, L. R., Prins, J. R. & Robertson, S. A. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Human reproduction update 15(5), 517\u2013535, https:\/\/doi.org\/10.1093\/humupd\/dmp004 (2009).","journal-title":"Human reproduction update"},{"issue":"19","key":"56336_CR7","doi-asserted-by":"publisher","first-page":"12293","DOI":"10.1073\/pnas.192461099","volume":"99","author":"Y Iwai","year":"2002","unstructured":"Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proceedings of the National Academy of Sciences of the United States of America 99(19), 12293\u201312297, https:\/\/doi.org\/10.1073\/pnas.192461099 (2002).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"56336_CR8","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/nri2326","volume":"8","author":"W Zou","year":"2008","unstructured":"Zou, W. & Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8, 467\u2013477, https:\/\/doi.org\/10.1038\/nri2326 (2008).","journal-title":"Nat Rev Immunol"},{"key":"56336_CR9","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1038\/nm863","volume":"9","author":"T Curiel","year":"2003","unstructured":"Curiel, T. et al. Blockade of B7-H1 improves myeloid dendritic cell\u2013mediated antitumor immunity. Nat Med 9, 562\u2013567, https:\/\/doi.org\/10.1038\/nm863 (2003).","journal-title":"Nat Med"},{"key":"56336_CR10","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1002\/cncr.24899","volume":"116","author":"R Hino","year":"2010","unstructured":"Hino, R. et al. Tumor cell expression of programmed cell death\u20101 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116, 1757\u20131766, https:\/\/doi.org\/10.1002\/cncr.24899 (2010).","journal-title":"Cancer"},{"issue":"127","key":"56336_CR11","doi-asserted-by":"publisher","first-page":"127ra37","DOI":"10.1126\/scitranslmed.3003689","volume":"4","author":"JM Taube","year":"2012","unstructured":"Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science translational medicine 4(127), 127ra37, https:\/\/doi.org\/10.1126\/scitranslmed.3003689 (2012).","journal-title":"Science translational medicine"},{"key":"56336_CR12","doi-asserted-by":"crossref","unstructured":"Patel, R., Bock, M., Polotti, C. F. & Elsamra, S. Pharmacokinetic drug evaluation of atezolizumab for the treatment of locally advanced or metastatic urothelial carcinoma. Expert Opin Drug Metab Toxicol. Feb;13(2):225\u2013232. Epub. Jan 11. doi:10.1080\/17425255.2017.1277204 (2017).","DOI":"10.1080\/17425255.2017.1277204"},{"issue":"52","key":"56336_CR13","doi-asserted-by":"publisher","first-page":"e5539","DOI":"10.1097\/MD.0000000000005539","volume":"95","author":"C Wang","year":"2016","unstructured":"Wang, C., Yu, X. & Wang, W. A meta-analysis of efficacy and safety of antibodies targeting PD-1\/PD-L1 in treatment of advanced nonsmall cell lung cancer. Medicine 95(52), e5539, https:\/\/doi.org\/10.1097\/MD.0000000000005539 (2016).","journal-title":"Medicine"},{"issue":"11","key":"56336_CR14","doi-asserted-by":"publisher","first-page":"e1005995","DOI":"10.1371\/journal.ppat.1005995","volume":"12","author":"M Nikolova","year":"2016","unstructured":"Nikolova, M. et al. Subset- and Antigen-Specific Effects of Treg on CD8+ T Cell Responses in Chronic HIV Infection. PLoS Pathogens 12(11), e1005995, https:\/\/doi.org\/10.1371\/journal.ppat.1005995 (2016).","journal-title":"PLoS Pathogens"},{"key":"56336_CR15","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/eji.200535458","volume":"36","author":"SC Liang","year":"2006","unstructured":"Liang, S. C. et al. PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis. Eur. J. Immunol. 36, 58\u201364, https:\/\/doi.org\/10.1002\/eji.200535458 (2006).","journal-title":"Eur. J. Immunol."},{"key":"56336_CR16","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/85330","volume":"2","author":"Y Latchman","year":"2001","unstructured":"Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2, 261\u2013268, https:\/\/doi.org\/10.1038\/85330 (2001).","journal-title":"Nat Immunol"},{"issue":"31","key":"56336_CR17","doi-asserted-by":"publisher","first-page":"11695","DOI":"10.1073\/pnas.0601347103","volume":"103","author":"Y Zhang","year":"2006","unstructured":"Zhang, Y. et al. Regulation of T cell activation and tolerance by PDL2. Proceedings of the National Academy of Sciences of the United States of America. 103(31), 11695\u201311700, https:\/\/doi.org\/10.1073\/pnas.0601347103 (2006).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America."},{"issue":"22","key":"56336_CR18","doi-asserted-by":"publisher","first-page":"9196","DOI":"10.1073\/pnas.1015298108","volume":"108","author":"R Bhadra","year":"2011","unstructured":"Bhadra, R., Gigley, J. P., Weiss, L. M. & Khan, I. A. Control of Toxoplasma reactivation by rescue of dysfunctional CD8\u2009+\u2009T-cell response via PD-1-PDL-1 blockade. Proceedings of the National Academy of Sciences of the United States of America 108(22), 9196\u20139201, https:\/\/doi.org\/10.1073\/pnas.1015298108 (2011).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"56336_CR19","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","volume":"12","author":"E Wherry","year":"2011","unstructured":"Wherry, E. T cell exhaustion. Nat Immunol 12, 492\u2013499, https:\/\/doi.org\/10.1038\/ni.2035 (2011).","journal-title":"Nat Immunol"},{"issue":"11","key":"56336_CR20","doi-asserted-by":"publisher","first-page":"e871","DOI":"10.1371\/journal.pntd.0000871","volume":"4","author":"J Hern\u00e1ndez-Ruiz","year":"2010","unstructured":"Hern\u00e1ndez-Ruiz, J. et al. CD8 cells of patients with diffuse cutaneous leishmaniasis display functional exhaustion: the latter is reversed. in vitro, by TLR2 agonists. PLoS neglected tropical diseases 4(11), e871, https:\/\/doi.org\/10.1371\/journal.pntd.0000871 (2010).","journal-title":"in vitro, by TLR2 agonists. PLoS neglected tropical diseases"},{"key":"56336_CR21","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.3389\/fimmu.2018.01021","volume":"9","author":"DH Barroso","year":"2018","unstructured":"Barroso, D. H. et al. PD-L1 May Mediate T-Cell Exhaustion in a Case of Early Diffuse Leishmaniasis Caused by Leishmania (L.) amazonensis. Frontiers in immunology 9, 1021, https:\/\/doi.org\/10.3389\/fimmu.2018.01021 (2018).","journal-title":"Frontiers in immunology"},{"issue":"7","key":"56336_CR22","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1128\/AAC.43.7.1776","volume":"43","author":"EC Torres-Santos","year":"1999","unstructured":"Torres-Santos, E. C., Rodrigues, J. M. Jr., Moreira, D. L., Kaplan, M. A. & Rossi-Bergmann, B. Improvement of in vitro and in vivo antileishmanial activities of 2\u2032, 6\u2032-dihydroxy-4\u2032-methoxychalcone by entrapment in poly(D,L-lactide) nanoparticles. Antimicrobial agents and chemotherapy 43(7), 1776\u20131778 (1999).","journal-title":"Antimicrobial agents and chemotherapy"},{"key":"56336_CR23","doi-asserted-by":"crossref","unstructured":"Pinheiro, R. O., Pinto, E. F., Benedito, A. B., Lopes, U. G. & Rossi-Bergmann, B. The T-cellanergy induced by Leishmania amazonensis antigens is related with defectiveantigen presentation and apoptosis. An Acad Bras Cienc. Sep;76(3):519\u201327.Epub. 10.1590\/S0001-37652004000300006 (2004).","DOI":"10.1590\/S0001-37652004000300006"},{"issue":"3","key":"56336_CR24","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/0014-4894(89)90120-3","volume":"68","author":"P Scott","year":"1989","unstructured":"Scott, P. The role of Th1 and Th2 cells in experimental cutaneous leishmaniasis. Exp. Parasitol. 68(3), 369\u2013372, https:\/\/doi.org\/10.1016\/0014-4894(89)90120-3 (1989).","journal-title":"Exp. Parasitol."},{"issue":"1","key":"56336_CR25","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1084\/jem.169.1.59","volume":"169","author":"FP Heinzel","year":"1989","unstructured":"Heinzel, F. P., Sadick, M. D., Holaday, B. J., Coffman, R. L. & Locksley, R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. The Journal of experimental medicine 169(1), 59\u201372, https:\/\/doi.org\/10.1084\/jem.169.1.59 (1989).","journal-title":"The Journal of experimental medicine"},{"issue":"6","key":"56336_CR26","first-page":"238","volume":"119","author":"A Awasthi","year":"2004","unstructured":"Awasthi, A., Mathur., R. K. & Saha, B. Immune response to Leishmania infection. Indian Journal of Medical Research. 119(6), 238\u2013258 (2004).","journal-title":"Indian Journal of Medical Research."},{"issue":"2","key":"56336_CR27","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1128\/iai.72.2.988-995.2004","volume":"72","author":"H Qi","year":"2004","unstructured":"Qi, H., Ji, J., Wanasen, N. & Soong, L. Enhanced replication of Leishmania amazonensis amastigotes in gamma interferon-stimulated murine macrophages: implications for the pathogenesis of cutaneous leishmaniasis. Infection and immunity 72(2), 988\u2013995, https:\/\/doi.org\/10.1128\/iai.72.2.988-995.2004 (2004).","journal-title":"Infection and immunity"},{"issue":"1","key":"56336_CR28","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13045-018-0582-8","volume":"11","author":"JA Marin-Acevedo","year":"2018","unstructured":"Marin-Acevedo, J. A. et al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. Journal of hematology & oncology. 11(1), 39, https:\/\/doi.org\/10.1186\/s13045-018-0582-8 (2018).","journal-title":"Journal of hematology & oncology."},{"issue":"26","key":"56336_CR29","doi-asserted-by":"publisher","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","volume":"366","author":"SL Topalian","year":"2012","unstructured":"Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of medicine 366(26), 2443\u20132454, https:\/\/doi.org\/10.1056\/NEJMoa1200690 (2012).","journal-title":"The New England journal of medicine"},{"key":"56336_CR30","doi-asserted-by":"publisher","first-page":"2455","DOI":"10.1056\/NEJMoa1200694","volume":"366","author":"JR Brahmer","year":"2012","unstructured":"Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 366, 2455\u20132465, https:\/\/doi.org\/10.1056\/NEJMoa1200694 (2012).","journal-title":"N Engl J Med."},{"issue":"7","key":"56336_CR31","doi-asserted-by":"publisher","first-page":"3380","DOI":"10.4049\/jimmunol.1202537","volume":"190","author":"ZM Mou","year":"2013","unstructured":"Mou, Z. M. et al. Parasite-derived arginase influences secondary anti-Leishmania immunity by regulating programmed cell death-1-mediated CD4+ T cell exhaustion. Journal of immunology (Baltimore, Md.:1950) 190(7), 3380\u20133389, https:\/\/doi.org\/10.4049\/jimmunol.1202537 (2013).","journal-title":"Journal of immunology (Baltimore, Md.:1950)"},{"issue":"11","key":"56336_CR32","doi-asserted-by":"publisher","first-page":"5542","DOI":"10.4049\/jimmunol.1301810","volume":"191","author":"KJ Esch","year":"2013","unstructured":"Esch, K. J., Juelsgaard, R., Martinez, P. A., Jones, D. E. & Petersen, C. A. Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function. Journal of immunology (Baltimore, Md.:1950) 191(11), 5542\u20135550, https:\/\/doi.org\/10.4049\/jimmunol.1301810 (2013).","journal-title":"Journal of immunology (Baltimore, Md.:1950)"},{"issue":"6","key":"56336_CR33","doi-asserted-by":"publisher","first-page":"e00019","DOI":"10.1128\/IAI.00019-18","volume":"86","author":"S Habib","year":"2018","unstructured":"Habib, S. et al. PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmania donovani. Infection and immunity. 86(6), e00019\u201318, https:\/\/doi.org\/10.1128\/IAI.00019-18 (2018).","journal-title":"Infection and immunity."},{"key":"56336_CR34","unstructured":"Shindo, Y. et al. Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. Anticancer Res. Jan;35(1):129\u201336 2015.."},{"key":"56336_CR35","doi-asserted-by":"crossref","unstructured":"Blake, S. J. P. et al. Blockade of PD-1\/PD-L1 Promotes Adoptive T-Cell Immunotherapy in a Tolerogenic Environment. Labrecque N, ed. PLoS One., 10(3):e0119483. 10.1371\/journal.pone.0119483 (2015).","DOI":"10.1371\/journal.pone.0119483"},{"issue":"1","key":"56336_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/CJI.0000000000000062","volume":"38","author":"KC Soares","year":"2015","unstructured":"Soares, K. C. et al. PD-1\/PD-L1 blockade together with vaccine therapy facilitates effector T cell infiltration into pancreatic tumors. Journal of immunotherapy. (Hagerstown, Md:1997). 38(1), 1\u201311, https:\/\/doi.org\/10.1097\/CJI.0000000000000062 (2015).","journal-title":"Journal of immunotherapy. (Hagerstown, Md:1997)."},{"key":"56336_CR37","doi-asserted-by":"publisher","unstructured":"Joshi, T. et al. B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections. PLoS Pathog. May;5(5): e1000431. https:\/\/doi.org\/10.1371\/journal.ppat.100043 (2009).","DOI":"10.1371\/journal.ppat.100043"},{"key":"56336_CR38","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1128\/iai.61.7.2952-2959.1993","volume":"61","author":"LC Afonso","year":"1993","unstructured":"Afonso, L. C. & Scott, P. Immune response associated with susceptibility of C57BL\/10 mice to Leishmania amazonensis. Infect Immun. 61, 2952\u20132959 (1993).","journal-title":"Infect Immun."},{"key":"56336_CR39","doi-asserted-by":"crossref","first-page":"5374","DOI":"10.4049\/jimmunol.158.11.5374","volume":"158","author":"L Soong","year":"1997","unstructured":"Soong, L. et al. Role of CD4+ T cells in pathogenesis associated with Leishmania amazonensis infection. J Immunol. 158, 5374\u20135383 (1997).","journal-title":"J Immunol."},{"issue":"2","key":"56336_CR40","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1128\/CVI.00456-09","volume":"17","author":"PM Boggiatto","year":"2010","unstructured":"Boggiatto, P. M. et al. Immunologic indicators of clinical progression during canine Leishmania infantum infection. Clinical and vaccine immunology: CVI 17(2), 267\u2013273, https:\/\/doi.org\/10.1128\/CVI.00456-09 (2010).","journal-title":"Clinical and vaccine immunology: CVI"},{"key":"56336_CR41","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.1210\/jc.2015-4227","volume":"101","author":"JJ Bastman","year":"2016","unstructured":"Bastman, J. J. et al. Tumor-infiltrating T Cells and the PD-1 checkpoint pathway in advanced differentiated and anaplastic thyroid cancer. Journal of Clinical Endocrinology & Metabolism. 101, 2863\u20132873, https:\/\/doi.org\/10.1210\/jc.2015-4227 (2016).","journal-title":"Journal of Clinical Endocrinology & Metabolism."},{"issue":"10","key":"56336_CR42","doi-asserted-by":"publisher","first-page":"e47648","DOI":"10.1371\/journal.pone.0047648","volume":"7","author":"G Nebbia","year":"2012","unstructured":"Nebbia, G. et al. Upregulation of the Tim-3\/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PloS one 7(10), e47648, https:\/\/doi.org\/10.1371\/journal.pone.0047648 (2012).","journal-title":"PloS one"},{"key":"56336_CR43","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1038\/nm1482","volume":"12","author":"L Trautmann","year":"2006","unstructured":"Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12, 1198\u20131202, https:\/\/doi.org\/10.1038\/nm1482 (2006).","journal-title":"Nat Med"},{"issue":"12","key":"56336_CR44","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1089\/jir.2015.0043","volume":"35","author":"MB Carneiro","year":"2015","unstructured":"Carneiro, M. B. et al. IFN-\u03b3-Dependent Recruitment of CD4(+) T Cells and Macrophages Contributes to Pathogenesis During Leishmania amazonensis Infection. J Interferon Cytokine Res. 35(12), 935\u2013947, https:\/\/doi.org\/10.1089\/jir.2015.0043 (2015).","journal-title":"J Interferon Cytokine Res."},{"key":"56336_CR45","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1126\/science.1636092","volume":"257","author":"M Barral-Netto","year":"1992","unstructured":"Barral-Netto, M. et al. Transforming growth factor-\u03b2 in leishmanial infection: a parasite escape mechanism. Science 257, 545\u2013548 (1992).","journal-title":"Science"},{"issue":"4","key":"56336_CR46","first-page":"947","volume":"147","author":"A Barral","year":"1995","unstructured":"Barral, A. et al. Transforming growth factor-\u03b2 in human cutaneous leishmaniasis. Am J Pathol. Oct 147(4), 947\u201354 (1995).","journal-title":"Am J Pathol. Oct"},{"issue":"13","key":"56336_CR47","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1016\/j.micinf.2005.04.016","volume":"7","author":"Roberta Olmo Pinheiro","year":"2005","unstructured":"Pinheiro, R. O. et al. TGF-\u03b2-associated enhanced susceptibility to leishmaniasis following intramuscular vaccination of mice with Leishmania amazonensis antigens. Microbes Infect. Oct;7(13):1317\u201323. Epub Jun 13. PubMed PMID: 16027022, (2005).","journal-title":"Microbes and Infection"},{"issue":"12","key":"56336_CR48","doi-asserted-by":"publisher","first-page":"3556","DOI":"10.1002\/1521-4141(200212)32:12<3556::AID-IMMU3556>3.0.CO;2-Q","volume":"32","author":"Mary?E. Wilson","year":"2002","unstructured":"Wilson, M. E. et al. The TGF-\u03b2 response to Leishmania chagasi in the absence of IL-12. Eur J Immunol. 32:3556\u20133565. [PubMed: 12516540] (2002).","journal-title":"European Journal of Immunology"},{"issue":"1","key":"56336_CR49","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.intimp.2014.02.027","volume":"20","author":"Shasha Song","year":"2014","unstructured":"Song, S. et al. Dendritic cells with an increased PD-L1 by TGF-\u03b2 induce T cell anergy for the cytotoxicity of hepatocellular carcinoma cells. International Immunopharmacology. Vol. 20, Issue 1, May, Pages 117\u2013123. https:\/\/doi.org\/10.1016\/j.intimp.2014.02.027 (2014).","journal-title":"International Immunopharmacology"},{"key":"56336_CR50","doi-asserted-by":"crossref","unstructured":"Padigel, U. M., Alexander, J. & Farrell, J .P. The role of interleukin-10 in susceptibility of BALB\/c mice to infection with Leishmania mexicana and Leishmania amazonensis. J Immunol. Oct 1;171(7):3705\u201310 (2003).","DOI":"10.4049\/jimmunol.171.7.3705"},{"key":"56336_CR51","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1084\/jem.20061141","volume":"204","author":"S Nylen","year":"2007","unstructured":"Nylen, S. et al. Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis. J Exp Med. 204, 805\u2013817 (2007).","journal-title":"J Exp Med."},{"issue":"1","key":"56336_CR52","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.exppara.2011.09.015","volume":"130","author":"Tania C. Felizardo","year":"2012","unstructured":"Felizardo, T. C., Gaspar-Elsas, M. I., Lima, G. M. & Abrahamsohn, I. A. Lack of signaling by IL-4 or by IL-4\/IL-13 has more attenuating effects on Leishmania amazonensis dorsal skin\u2013than on footpad-infected mice. Exp Parasitol Jan; 130(1):48\u201357. https:\/\/doi.org\/10.1016\/j.exppara.2011.09.015 (2011).","journal-title":"Experimental Parasitology"},{"issue":"3","key":"56336_CR53","doi-asserted-by":"publisher","first-page":"e0007152","DOI":"10.1371\/journal.pntd.0007152","volume":"13","author":"Stephen M. Christensen","year":"2019","unstructured":"Christensen, S. M. et al Host and parasite responses in human diffuse cutaneous leishmaniasis caused by L. amazonensis. PLoS Negl Trop Dis. Mar 7;13(3):e0007152. https:\/\/doi.org\/10.1371\/journal.pntd.0007152 (2019).","journal-title":"PLOS Neglected Tropical Diseases"},{"key":"56336_CR54","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1084\/jem.191.6.1063","volume":"191","author":"PE Kima","year":"2000","unstructured":"Kima, P. E. et al. Internalization of Leishmania mexicana complex amastigotes via the Fc receptor is required to sustain infection in murine cutaneous leishmaniasis. Journal of Experimental Medicine. 191, 1063\u20131067 (2000).","journal-title":"Journal of Experimental Medicine."},{"key":"56336_CR55","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.cellimm.2018.08.014","volume":"334","author":"Luan Firmino-Cruz","year":"2018","unstructured":"Firmino-Cruz, L., et al. Immunomodulating role of IL-10-producing B cells in Leishmania amazonensis infection. Cell Immunol. Aug 22. pii: S0008\u20138749(18)30261-2. https:\/\/doi.org\/10.1016\/j.cellimm.2018.08.014 (2018).","journal-title":"Cellular Immunology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-56336-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-56336-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-56336-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T13:27:23Z","timestamp":1695562043000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-56336-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,30]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["56336"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-56336-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,30]]},"assertion":[{"value":"12 August 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20275"}}