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T-cell immune responses are required to mount anti-mycobacterial immunity. However, T-cell immune responses modulated by programmed cell death protein 1 (PD-1) during tuberculosis pleurisy (TBP) remains poorly understood. We selected the pleural fluid mononuclear cells (PFMCs) from TBP and PBMCs from healthy donors (HD), and characterized PD-1-expresing T-cell phenotypes and functions. Here, we found that the PFMCs exhibited increases in numbers of PD-1-expressing CD4+ and CD8+ T cells, which preferentially displayed polarized effector memory phenotypes. The M.tb-specific Ag stimulation increased CD4+PD-1+ and CD8+PD-1+ T cells, which is in direct correlation with IFN-\u03b3 production and PD-L1+ APCs in PFMCs of these individuals. Moreover, blockage of PD-1\/PD-L1 pathway enhanced the percentage of IFN-\u03b3+ T cells, demonstrating that the PD-1\/PD-L1 pathway played a negative regulation in T cell effector functions. Furthermore, CD4+PD-1+ and CD8+PD-1+ T-cell subsets showed greater memory phenotype, activation, and effector functions for producing Th1 cytokines than PD-1\u2212 counterparts. Thus, these PD-1+ T cells were not exhausted but appear to be central to maintaining Ag-specific effector. IL-12, a key immunoregulatory cytokine, enhanced the expression of PD-1 and restored a strong IFN-\u03b3 response through selectively inducing the phosphorylation of STAT4 in CD4+PD-1+T-bet+ and CD8+PD-1+T-bet+ T cells. This study therefore uncovered a previously unknown mechanism for T-cell immune responses regulated by PD-1, and may have implications for potential immune intervention in TBP.<\/jats:p>","DOI":"10.1002\/jlb.ma1118-450rr","type":"journal-article","created":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T16:21:23Z","timestamp":1552407683000},"page":"733-747","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["PD-1 modulating <i>Mycobacterium tuberculosis<\/i>-specific polarized effector memory T cells response in tuberculosis pleurisy"],"prefix":"10.1093","volume":"106","author":[{"given":"Jiangping","family":"Li","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital, Guangzhou Medical University , Guangzhou, P. R. China"},{"name":"Institute of Immunology, Sun Yat-sen University , Guangzhou, P. R. China"},{"name":"State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center , Guangzhou, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Jin","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital, Guangzhou Medical University , Guangzhou, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyou","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Sun Yat-sen University , Guangzhou, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Huang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital, Guangzhou Medical University , Guangzhou, P. R. 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