Attenuation of lymphocyte immune responses during Mycobacterium avium complex-induced lung disease due to increasing expression of programmed death-1 on lymphocytes

Chin-Chung Shu,Bor-Luen Chiang,Hsin-Chih Lai,Li-Na Lee,Chong-Jen Yu,Ming-Fang Wu,Chen-Tu Wu,Jann-Yuan Wang

doi:10.1038/srep42004

Abstract

Mycobacterium avium complex-induced lung disease (MAC-LD) becomes important due to its increasing prevalence. Attenuated cellular immunity associated with programmed cell death (PD)–1 may play a pathophysiological role in MAC-LD but lacks of investigation. We enrolled 80 participants in this prospective study, including 50 with MAC-LD and 30 healthy controls. Peripheral blood mononuclear cells (PBMCs), lymphocytes and monocyte-derived macrophages were used for MAC antigen stimulation. Patients with MAC-LD had lower tumor necrosis factor-α and interferon-γ responses compared to the healthy controls in PBMC stimulation assays with MAC bacilli. These responses improved after MAC treatment. The PD-1 and PD ligand expressions and apoptosis were higher in the lymphocytes of the patients with MAC-LD compared to the controls. Both PD-1 and apoptosis on T lymphocytes were significantly increased in the patients with MAC-LD, either by direct MAC stimulation or by MAC-primed macrophage activation. Partially blocking PD-1 and the PD ligand with antagonizing antibodies in the stimulation assay significantly increased the cytokine production of IFN-γ and decreased the apoptosis on T lymphocytes. In conclusion, the patients with MAC-LD have attenuated lymphocyte immunity, which might be associated with increasing activation of PD-1 and PD-1 ligand. Regulating such activation might improve the lymphocytic secretion of IFN-γ and reduce apoptosis.

Highlights

T cell activation, and it sends inhibitory signals to control the inflammation threshold for antigen stimulation[16]
The results showed that the expression of PD-1 was higher in CD3, CD4 (36.5 ± 14.1% vs. 23.8 ± 5.3%, p = 0.007), CD8 (34.1 ± 9.9% vs. 23.5 ± 8.3%, p = 0.008), CD19 (3.5 ± 2.2% vs. 2.1 ± 1.1%, p = 0.029), CD56 (10.4 ± 10.5% vs. 3.9 ± 2.5%, p = 0.028), and CD4+CD25+cells (50.4 ± 18.1% vs. 30.5 ± 9.9%, p = 0.023) of the patients with Mycobacterium avium complex (MAC)-LD compared to the healthy controls (Fig. 2A–C, Mann Whitney U test)
Given the higher expression of PD-1/PD-L1 on the lymphocytes of the patients with MAC-LD, and that the PD-1 expression and apoptosis were responsive to MAC stimulation, we investigated whether a high expression of the PD-1 pathway on lymphocytes in the patients with MAC-LD was responsible for the decrease in cytokine production and increase in apoptosis

Summary

Introduction

T cell activation, and it sends inhibitory signals to control the inflammation threshold for antigen stimulation[16]. Once PD-1 is over-expressed in patients with chronic mycobacterial lung disease, apoptosis will increase and cellular immunity will be attenuated[17,18,19]. Under such conditions of suppressed immunity, MAC bacilli may progress to infection as they enter the airway[20]. The PD-1 pathway in the pathogenesis of MAC-LD has yet to be investigated. The aim of this study was to investigate the pathogenic role of PD-1 in MAC-LD

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Methods

Results

Conclusion