Ana Villasenor Altamirano, PhD
Pulmonary and Clinical Care Medicine
Ana B Villaseñor Altamirano*, Dhawal Jain*, Yunju Jeong, Hibah Haider, Reshmi Manandhar, Jaivardhan A Menon, Muhammad Dawood Amir Sheikh, Humra Athar, Louis T. Merriam, Craig P. Hersh, Xiaobo Zhou, Justus Veerkamp**, Jeong H. Yun**, Edy Kim**
Rationale: Despite the importance of inflammation chronic obstructive pulmonary disease (COPD), inflammation in lung tissue from patients with mild-moderate COPD has not been well described at the molecular and single-cell level.
Objectives: We apply a multi-omic, single-cell approach to define inflammation in lung tissue from patients with mild-moderate COPD.
Methods: We performed single-cell transcriptomics (RNA-seq) and proteomics (CITE-seq) on lung tissue from patients with mild-moderate COPD (n=5, GOLD I/II) compared to control (n=5), emphysema without airﬂow obstruction (n=5), and “end-stage” COPD lung explants. We examine enriched cell clusters and their interactome. We integrated our dataset with public scRNA-seq datasets of explanted COPD lung and a murine model of COPD driven by Hhip(+/-). We validated our findings in a lung bulk RNA-seq dataset from an independent patient cohort (N=316).
Measurements and Main Results: Mild-moderate COPD lungs are enriched in two CD8+ T cell populations: 1)KLRG1+ TEMRA cells expressing cytotoxicity, TIGIT, and CX3CR1; and 2)T resident memory (TRM) cells expressing long-term memory, PD-1, TACTILE, and CCR5. These CD8+ T cell subsets interact with monocytes via IFNG, TNFA, and ANXA1-FPR1 axes. In an independent cohort, the gene signature for CD8+ KLRG1+ TEMRA cells is increased in GOLD I/II COPD compared to control or GOLD III/IV patients. In cross-species comparison, these cells resemble CD8+ KLRG1+ T cells implicated in experimental COPD.
Conclusions: CD8+ KLRG1+ TEMRA and TRM cells are increased in mild-moderate COPD lung and may contribute to inflammation that precedes severe disease.
Multi-omic single-cell approaches have identified functional lymphoid subsets in both normal and diseased lung, but multi-omic single-cell has not been applied to COPD. Here, we characterize the molecular pathways that distinguish mild-moderate COPD from severe COPD. We applied a multi-omic approach using single-cell transcriptomics and proteomics to lung tissue from patients with mild-moderate COPD (GOLD I/II), and we compare to emphysema without airway obstruction, patients with “end-stage” COPD undergoing lung transplantation, and controls. Two CD8+ T cell subpopulations, KLRG1+ TEMRA cells and T resident memory 1 (TRM1), were more abundant in mild-moderate COPD lung tissue when compared to other patient sub cohorts. KLRG1+ CD8+ TEMRA and TRM1 cells were associated with COPD and IFNγ response, suggesting cell markers for stage disease.