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

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.

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

“…29 In tuberculous pleural effusions, PD-1-expressing CD4 + and CD8 + T cells had activated phenotype and increased production of Th1 cytokines compared with PD-1 − cells. 30 Our study found a subset of PD-1 high CXCR5 − MAIT cells that were expanded in tuberculous pleural effusions. Although PD-1 high CXCR5 − MAIT cells from tuberculous pleural effusions had reduced IFN-γ level and increased expression of Tim-3 and GITR, they showed activated phenotype and higher glucose uptake and lipid content, suggesting that Mtb infection might promote reprogramming of MAIT cells.…”

“…Treatment of patients with cancer by anti‐PD‐1 blockage led to increased risk of TB in humans . In tuberculous pleural effusions, PD‐1‐expressing CD4 + and CD8 + T cells had activated phenotype and increased production of Th1 cytokines compared with PD‐1 − cells . Our study found a subset of PD‐1 high CXCR5 − MAIT cells that were expanded in tuberculous pleural effusions.…”

Cross-Talk Between Alveolar Macrophages and Lung Epithelial Cells is Essential to Maintain Lung Homeostasis

“…This regulation affects other immune cells such as T cells and dendritic cells that also express CD200R ( 150 ). Similarly, the binding of PDL-1 to its receptor PD-1 dampens AM secretion of inflammatory cytokines and negatively regulates T cell effector functions ( 151 , 152 ), whereas binding of CD47 to SIRP1α expressing macrophages downregulate phagocytosis ( 153 , 154 ). Thus, there is a breadth of evidence demonstrating the importance of lung ECs in regulating local immune responses, by interacting/communicating with immune cells, including AMs.…”

Th22 response induced byMycobacterium tuberculosisstrains is closely related to severity of pulmonary lesions and bacillary load in patients with multi-drug-resistant tuberculosis

“…Sustained high expression of PD‐1 has been associated with T cell dysfunction in chronic viral infections and tumors [39]. In human TB, high PD‐1 expression has been observed in T cells from peripheral blood and pleural effusion of patients with TB pleurisy [40] and in circulating CD4 + T cells from S‐TB patients with a positive AFB sputum smear [24]. In our study, we observed a marked increase in the percentage of CD4 + and CD8 + PD‐1 + cells in MDR‐TB compared to S‐TB patients, despite 92% of MDR‐TB and all S‐TB patients having a positive sputum smear at the time of the study.…”