PD-1/PD-L pathway inhibits M.tb-specific CD4+ T-cell functions and phagocytosis of macrophages in active tuberculosis

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.

PD‐1‐expressing MAIT cells from patients with tuberculosis exhibit elevated production of CXCL13

“…Expression of PD‐1 on T cells, MAIT cells and NK cells from patients with TB was elevated, and blockage of PD‐1 and/or its ligands improves functions of T cells, MAIT cells and NK cells . PD‐1 expression on Mtb ‐specific CD4 T cells correlates with bacterial load and decreases after successful anti‐TB drug treatment . Bronchoalveolar lavage from patients with military TB had significantly higher PD‐1 + T cells with diminished production of IFN‐γ and TNF‐α .…”

“…15,16,[21][22][23] PD-1 expression on Mtb-specific CD4 T cells correlates with bacterial load and decreases after successful anti-TB drug treatment. 24,25 Bronchoalveolar lavage from patients with military TB had significantly higher PD-1 + T cells with diminished production of IFN-γ and TNF-α. 26 Although PD-1 −/− mice had highly enhanced Th1 responses during Mtb infection, they showed severe and lethal immunopathology.…”

PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity

“…The PD-1 receptor is one of the best-studied and most clinically successful immune checkpoint drug targets, but its primary function is widely understood to be in the regulation of T cells. However, given that macrophages have previously been reported to express PD-1 in the context of pathogen infection, 14–17 we wondered whether macrophages might also express PD-1 in the tumor microenvironment, and if so, what consequences this expression might have on anti-tumor immunity.…”

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

“…In fact, there are several signaling proteins contributing to the active up‐ or down‐regulation during the priming of a T cell immune response . Programmed cell death protein 1 (PD‐1), a membrane protein that is an inhibitory receptor from the CD28 family, is initially identified as a negative regulator of Th1‐type immunity in humans and mice . While PD‐1 is not expressed on naïve T cells, it is up‐regulated following TCR‐mediated activation and is readily observed on both activated and exhausted T cells .…”

“…8,11,12 Programmed cell death protein 1 (PD-1), a membrane protein that is an inhibitory receptor from the CD28 family, is initially identified as a negative regulator of Th1-type immunity in humans and mice. 13,14 While PD-1 is not expressed on naïve T cells, it is up-regulated following TCR-mediated activation and is readily observed on both activated and exhausted T cells. 10 It shows that PD-1, like other members of T-cell inhibitory molecules such as T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) and co-stimulatory receptor cytotoxic T-lymphocyte Ag-4 (CTLA-4), may represent a negative regulator in T-cell immune response during chronic infections.…”