Abstract
The role of the PD-1/PD-L pathway in a murine model of tuberculosis remains controversial regarding viral infections and clinical tuberculosis. We conducted a case-control study to investigate the modulating role and mechanism of the PD-1/PD-L pathway in patients with active tuberculosis. Fifty-nine participants, including 43 active tuberculosis (ATB) patients and 16 healthy controls (HC), were enrolled. Cell surface staining and flow cytometry were used to detect the expressions of PD-1 and its ligands on T cells and monocytes. Intracellular cytokine staining was used to determine the PPD-specific IFN-γ-secreting T-cell proportion. CD4+ T-cell proliferation and macrophage functions were investigated in the presence or absence of PD-1/PD-L pathway blockade. Proportions of both PD-1+CD4+ and PD-L1+CD4+ T cells in ATB patients were more significantly increased than in the HC group (P = 0.0112 and P = 0.0141, respectively). The expressions of PD-1, PD-L1, and PD-L2 on CD14+ monocytes in ATB patients were much higher than those in the HC group (P = 0.0016, P = 0.0001, and P = 0.0088, respectively). Blockade of PD-1 could significantly enhance CD4+ T-cell proliferation (P = 0.0433). Phagocytosis and intracellular killing activity of macrophages increased significantly with PD-1/PD-L pathway blockade. In conclusion, the PD-1/PD-L pathway inhibits not only M.tb-specific CD4+ T-cell-mediated immunity but also innate immunity.
Highlights
IntroductionThe PD-1/PD-L pathway includes PD-1 ( known as CD279) and its two ligands: PD-L1 ( known as CD274 and B7-H1) and PD-L2 ( known as CD273 and B7-DC), which are type I transmembrane proteins belonging to the CD28 superfamily
The PD-1/PD-L pathway includes PD-1 and its two ligands: PD-L1 and PD-L2, which are type I transmembrane proteins belonging to the CD28 superfamily
The 59 enrolled participants were divided into two groups: the active tuberculosis (ATB) group (n = 43), which included patients with confirmed active pulmonary tuberculosis (n = 19) and tuberculosis pleurisy (n = 24), and the healthy control (HC) group (n = 16)
Summary
The PD-1/PD-L pathway includes PD-1 ( known as CD279) and its two ligands: PD-L1 ( known as CD274 and B7-H1) and PD-L2 ( known as CD273 and B7-DC), which are type I transmembrane proteins belonging to the CD28 superfamily. PD-1 and its role in T-cell exhaustion were initially determined in microarray studies that screened the gene expression difference in murine CD8+ T cells between acute and chronic lymphocytic choriomeningitis virus (LCMV) infection[9]. In human virus infection, such as human immunodeficiency virus (HIV)[10] and hepatitis C virus (HCV)[11], the PD-1 pathway mediates T-cell exhaustion, which can be restored www.nature.com/scientificreports/. Overexpression of PD-1 and its ligands on T cells, NK cells, and macrophages of patients with tuberculosis as well as its inhibitory role in innate and adaptive immunity have been reported[12,13]. The exact mechanism of inhibiting the T-cell response and macrophage function against M.tb has yet to be elucidated. We conducted a case-control study using an in vitro system to investigate the modulating role and mechanism of the PD-1/PD-L pathway in active tuberculosis
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