Abstract Background Granzyme K (GZMK) expressing CD8 T cells are pro-inflammatory cells enriched in asthma, bronchiolitis obliterans syndrome and autoimmune diseases. These cells activate complement cascade leading to persistent inflammation, however their characteristics have not been comprehensively studied in different chronic lung diseases. We hypothesized that GZMK+ CD8 T cells are differentially abundant across chronic lung disease subtypes and investigated the expression of GZMK+CD8 T cell signatures. Methods We analyzed bulk lung tissue RNA sequencing data from the Lung Tissue Research Consortium, across different disease pathologies including controls (n = 340), chronic obstructive pulmonary disease (COPD, n = 505), combined pulmonary fibrosis and emphysema (CPFE, n = 43), smoking-related interstitial lung disease (smoking-ILD, desquamative interstitial pneumonia DIP, respiratory bronchiolitis RB-ILD, n = 16) and other ILDs (n = 340). We used a top 15-gene signature derived from GZMK+ CD8 T cells identified in single cell RNA-seq data and calculated enrichment scores to quantify the GZMK+CD8 T cell signature score for each subject using gene set variation analysis. We performed linear regression models adjusted for age, sex, race, smoking pack years and current smoking status. Results The lung GZMK+CD8 T cell score correlated with blood lymphocyte percentage (Pearson r = 0.2, p 0.003) and cumulative smoking (pack years, r = 0.23, p = 0.0006). In multivariable models, GZMK+CD8 T cell signature scores were significantly elevated in COPD compared to controls (adjusted mean difference β = 0.1, Tukey-adj. p = 0.003). Among smoking related pathologies, there was no statistical difference between COPD and CPFE, however smoking-related ILD had the highest GZMK+CD8 T cell score with marginal significance (vs. controls β = 0.28, adj. p = 0.06). Among ILD pathology subtypes, usual interstitial pneumonia (UIP, n = 186) had the lowest score while organizing pneumonia (n = 18) had the highest score. Notably, GZMK+CD8 T cell score was positively correlated with DLCO in CPFE(r = 0.3, p = 0.09) but negatively correlated in smoking-ILD (r= -0.5, p = 0.09), suggesting distinct immunological patterns across disease pathology. Conclusions GZMK+CD8 T cell signatures are elevated in COPD and show heterogeneous enrichment patterns across chronic lung disease subtypes. The highest scores in organizing pneumonia and smoking-related ILD, as well as the positive correlation with disease severity (DLCO) in smoking-related ILD suggest GZMK+CD8 T cells may be enriched in airway-centric diseases involving inflammation. This abstract is funded by: K08HL146972
Yun et al. (Fri,) studied this question.