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We aimed to study the role of PD-1 pathway and macrophage polarization on <jats:italic>Mtb<\/jats:italic>-specific CD8<jats:sup>+<\/jats:sup>T cell-induced macrophage death. We observed that both PD-L1 on CD14<jats:sup>+<\/jats:sup> cells and PD-1 on CD8<jats:sup>+<\/jats:sup>T cells were highly expressed at the site of infection in pleurisy TB patients\u2019 effusion samples (PEMC). Moreover, a significant increase in CD8<jats:sup>+<\/jats:sup>T cells\u2019 <jats:italic>Mtb<\/jats:italic>-specific degranulation from TB-PEMC vs. TB-PBMC was observed, which correlated with PD-1 and PDL-1 expression. In an <jats:italic>in vitro<\/jats:italic> model, M1 macrophages were more susceptible to <jats:italic>Mtb<\/jats:italic>-specific CD8<jats:sup>+<\/jats:sup>T cells\u2019 cytotoxicity compared to M2a macrophages and involved the transfer of cytolytic effector molecules from CD8<jats:sup>+<\/jats:sup>T lymphocytes to target cells. Additionally, PD-L1 blocking significantly increased the <jats:italic>in vitro<\/jats:italic> Ag-specific CD8<jats:sup>+<\/jats:sup>T cell cytotoxicity against IFN-\u03b3-activated macrophages but had no effect over cytotoxicity on IL-4 or IL-10-activated macrophages. Interestingly, PD-L1 blocking enhanced <jats:italic>Mtb<\/jats:italic>-specific CD8<jats:sup>+<\/jats:sup> T cell killing of CD14<jats:sup>+<\/jats:sup> cells from human tuberculous pleural effusion samples. Our data indicate that PD-1\/PD-L1 pathway modulates antigen-specific cytotoxicity against M1 targets <jats:italic>in-vitro<\/jats:italic> and encourage the exploration of checkpoint blockade as new adjuvant for TB therapies.<\/jats:p>","DOI":"10.1038\/s41598-018-36403-2","type":"journal-article","created":{"date-parts":[[2019,1,12]],"date-time":"2019-01-12T07:46:13Z","timestamp":1547279173000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["PD-1\/PD-L1 Pathway Modulates Macrophage Susceptibility to Mycobacterium tuberculosis Specific CD8+ T cell Induced Death"],"prefix":"10.1038","volume":"9","author":[{"given":"Guadalupe Ver\u00f3nica","family":"Suarez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia del Carmen","family":"Melucci Ganzarain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5408-5922","authenticated-orcid":false,"given":"Mar\u00eda Bel\u00e9n","family":"Vecchione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar Ariel","family":"Trifone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Luis","family":"Mar\u00edn Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Genoula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Jos\u00e9","family":"Mora\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Balboa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0956-5492","authenticated-orcid":false,"given":"Maria Florencia","family":"Quiroga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,1,17]]},"reference":[{"key":"36403_CR1","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/nrmicro2387","volume":"8","author":"SM Behar","year":"2010","unstructured":"Behar, S. 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