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PD-1 modulating Mycobacterium tuberculosis-specific polarized effector memory T cells response in tuberculosis pleurisy

Jiangping Li, Chenxi Jin, Changyou Wu, Jun Huang
Journal of Leukocyte Biology 2019 March 12
Host-pathogen interactions in tuberculosis (TB) should be studied at the disease sites because Mycobacterium tuberculosis (M.tb) is predominantly contained in local tissue lesions. 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-γ production and PD-L1+ APCs in PFMCs of these individuals. Moreover, blockage of PD-1/PD-L1 pathway enhanced the percentage of IFN-γ+ 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- 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-γ 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.


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