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

摘要

Abstract 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.