MAIT cell counts are associated with the risk of hospitalization in COPD

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation associated with chronic inflammation in the airways. Mucosal-associated invariant T (MAIT) cells are unconventional, innate-like T cells highly abundant in mucosal tissues including the lung. We hypothesized that the characteristics of MAIT cells in circulation may be prospectively associated with COPD morbidity.

Methods: COPD subjects (n = 61) from the Tools for Identifying Exacerbations (TIE) study were recruited when in stable condition. At study entry, forced expiratory volume in 1 s (FEV₁) was measured and peripheral blood mononuclear cells were cryopreserved for later analysis by flow cytometry. Patients were followed for 3 years to record clinically meaningful outcomes.

Results: Patients who required hospitalization at one or more occasions during the 3-year follow-up (n = 21) had lower MAIT cell counts in peripheral blood at study inclusion, compared with patients who did not get hospitalized (p = 0.036). In contrast, hospitalized and never hospitalized patients did not differ in CD8 or CD4 T cell counts (p = 0.482 and p = 0.221, respectively). Moreover, MAIT cells in hospitalized subjects showed a more activated phenotype with higher CD38 expression (p = 0.014), and there was a trend towards higher LAG-3 expression (p = 0.052). Conventional CD4 and CD8 T cells were similar between the groups. Next we performed multi-variable logistic regression analysis with hospitalizations as dependent variable, and FEV₁, GOLD 2017 group, and quantity or activation of MAIT and conventional T cells as independent variables. MAIT cell count, CD38 expression on MAIT cells, and LAG-3 expression on both MAIT and CD8 T cells were all independently associated with the risk of hospitalization.

Conclusions: These findings suggest that MAIT cells might reflect a novel, FEV₁-independent immunological dimension in the complexity of COPD. The potential implication of MAIT cells in COPD pathogenesis and MAIT cells' prognostic potential deserve further investigation.

Keywords: COPD; Human; Immune activation; MAIT cells; T cells.

Fig. 1

Gating strategy. A Gating strategy to identify peripheral blood CD4 T cells, classical CD8 T cells, MAIT cells and expression of the activation markers CD38 and LAG-3 on MAIT cells. Gates for CD38 and LAG-3 expression on MAIT cells (orange) were set based on the expression on total T cells (in grey) when a clear negative and positive population could be identified or based on the unstained control (black) otherwise. MAIT cells were identified as CD4-Vα7.2 + CD161 + T cells. For quantification of classical CD8 T cells, MAIT cells were gated out. B Phenotypic comparison of MAIT cells in COPD patients requiring hospitalization or not during the 3-year follow-up. Representative flow cytometry staining of TIM-3, PD1, HLA-DR, CD56, CCR5 and TIGIT on MAIT cells (orange) using the unstained control (black) or the total T cells (grey) as controls to set the gate. The scatter plots display the expression of each marker (median ± IQR) on MAIT cells between Hospitalized (n = 21) and Never Hospitalized (n = 40) COPD patients during the 3-year follow-up. The Mann–Whitney U Test was used to evaluate statistical differences between groups

Fig. 2

MAIT cell count and expression of the activation marker CD38 are associated with the risk of hospitalization. MAIT cell count, CD8 T cell count, CD4 T cell count (A), MAIT cell percentage, CD8 T cell percentage, CD4 T cell percentage (B), CD38 expression on MAIT cells, CD38 expression on CD8 T cells (C), LAG-3 expression on MAIT cells, and LAG-3 expression on CD8 T cells (D) in COPD subjects who required hospitalization during the 3-year follow-up (n = 21), compared to subjects who were not hospitalized (n = 40). Mann–Whitney U Test in all. Bars represent median with interquartile range

Fig. 3

MAIT cell level and phenotype do not correlate with lung function. Relationship between MAIT cell percentage among the live CD3 + population (A), MAIT cell count (B), CD38 expression on MAIT cells (C), LAG-3 expression on MAIT cells (D), and forced expiratory volume in 1 s (FEV1) in the studied COPD cohort. Spearman correlation analysis. N = 61 in all. r_s: correlation coefficient; p: p-value