Physical activity attenuates PD-1/PD-L1 expression and enhances CD4⁺ T-cell function in COPD patients

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation, immune dysregulation, and T-cell dysfunction. The PD-1/PD-L1 immune checkpoint axis is implicated in immune exhaustion and increased exacerbation risk in COPD. Physical activity (PA) is known to exert anti-inflammatory effects, yet its impact on immune checkpoint regulation remains unclear. We aimed to evaluate the association between PA and PD-1/PD-L1 expression in COPD and assess whether a structured PA intervention modulates this axis and improves T-cell function. Ninety-one patients with stable COPD were classified by baseline physical activity level (PAL) using a multiparametric accelerometer. Plasma PD-1/PD-L1 levels, peripheral blood mononuclear cell expression, and T-cell proliferation were assessed pre-and-post-intervention. Sedentary patients showed elevated plasma PD-1/PD-L1 and increased expression in CD4⁺ T cells and monocytes, correlating inversely with activity and CD4⁺ T-cell proliferation. Following the intervention, patients with improved PAL exhibited significant reductions in PD-1 and enhanced CD4⁺ T-cell proliferation. These effects were not observed in CD8⁺ cells, which responded primarily to PD-1 blockade. Physical activity is associated with lower PD-1/PD-L1 expression and improved CD4⁺ T-cell function in COPD. A structured PA intervention may modulate immune checkpoint pathways, offering a non-pharmacologic strategy to restore immune competence.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-025-31223-7.

Keywords: COPD; Immune checkpoint; PD-1; PD-L1; Physical activity level; T-cells.

Fig. 1

Association between physical activity and plasma levels of soluble PD-1 and PD-L1 in COPD patients. (A) Plasma PD-1 and (B) PD-L1 concentrations in COPD patients stratified by physical activity level (PAL): moderate activity (MA, n = 21), moderate sedentarism (MS, n = 41), and severe sedentarism (SS, n = 27). (C–D) Spearman’s correlation between plasma levels of PD-1 (C) or PD-L1 (D) and objective physical activity parameters (n = 89). Spearman’s rho (ρ) and p-values are shown. (E–F) Plasma concentrations of PD-1 (E) and PD-L1 (F) in patients with no exacerbations in the previous year (n = 64) versus those with ≥ 1 moderate-to-severe exacerbation (n = 25). Data are presented as medians with 95% confidence intervals. Differences are analyzed by Kruskal–Wallis test with Dunn’s post hoc correction; adjusted p-values are indicated.

Fig. 2

Expression of PD-1/PD-L1 and T-cell proliferative capacity according to physical activity levels in COPD patients. Patients were stratified by physical activity level (PAL) into three groups: moderate activity (MA; PAL > 1.65, yellow), moderate sedentary (MS; PAL 1.35–1.65, orange), and severe sedentary (SS; PAL < 1.35, red). (A) Frequency of PD-1–expressing CD4⁺ T cells (left) and CD8⁺ T cells (right) in MA (n = 20), MS (n = 40), and SS (n = 25) groups. (B) Frequency of PD-L1–expressing CD14⁺ monocytes in the same patient groups. (C) Proliferation of CD4⁺ (left) and CD8⁺ (right) T cells from peripheral blood mononuclear cells (PBMCs) after 96 h stimulation with 2 µg/mL pokeweed mitogen in MA (n = 19), MS (n = 36), and SS (n = 20) patients. (D) Correlation matrix between CD4⁺ and CD8⁺ T-cell proliferation and clinical, physical activity, and immune parameters (n = 75). Only significant Spearman’s correlations (P < 0.05) are shown. (E) T-cell proliferation (CD4⁺, left; CD8⁺, right) following 96 h culture under basal conditions or with PD-1 blockade (Nivolumab) in MA (n = 9), MS (n = 12), and SS (n = 10) groups. Paired data are shown. Data are presented as medians with 95% confidence intervals. Differences are analyzed using Kruskal–Wallis tests with Dunn’s post hoc correction or Wilcoxon matched-pairs signed-rank test, as appropriate. Adjusted P values are shown; n.s., not significant.

Fig. 3

Modulation of PD-1/PD-L1 axis expression following a physical activity intervention in COPD patients. Patients were categorized based on the change in physical activity level (PAL) after intervention: decreased activity (ΔPAL ≤ 0, n = 23) and increased activity (ΔPAL > 0, n = 36). (A) Plasma concentrations of soluble PD-1 and (B) PD-L1 before and after the intervention. (C–E) Frequency of PD-1⁺ CD4⁺ T cells (C), PD-1⁺ CD8⁺ T cells (D), and PD-L1⁺ CD14⁺ monocytes (E) pre- and post-intervention in patients who decreased (n = 23) or increased (n = 32) their PAL. Data are presented as medians with 95% confidence intervals. Comparisons were performed using two-way ANOVA with Sidak’s multiple comparisons test. Adjusted and interaction P values are reported; n.s., not significant.

Fig. 4

T-cell proliferative responses before and after a physical activity intervention in COPD patients. T-lymphocyte proliferation was assessed in peripheral blood mononuclear cells (PBMCs) collected pre- (orange) and post-intervention (green). (A–B) Proliferative CD4⁺ (A) and CD8⁺ (B) T-cell responses after 96 h stimulation with 2 µg/mL pokeweed mitogen in patients who decreased (ΔPAL ≤ 0, n = 17) or increased (ΔPAL > 0, n = 19) their physical activity level. (C–D) CD4⁺ (C) and CD8⁺ (D) T-cell proliferation pre- and post-intervention, cultured for 96 h under basal conditions or in the presence of a PD-1 blocking antibody (Nivolumab) (n = 21). Data are presented as medians with 95% confidence intervals. Statistical analysis was performed using two-way ANOVA with Sidak’s multiple comparisons test. Adjusted and interaction P values are shown; n.s., not significant.