Bad Neighbors or Bad Neighborhoods: Pathogenic Residency of T Cells in Chronic Obstructive Pulmonary Disease

The lung is an incredibly diverse cellular neighborhood, composed of structural cell types present since embryonic specification along with circulating cell types that take up residency later in life. The lung’s capacity to host circulating immune cells allows a rapid response to pathogens at the site of entry, particularly adaptive immune cells such as T cells that can take up residency in the organ and impart immunologic memory to foreign antigens (1). However, hosting resident immune cells comes with a cost because these cells provoke inflammatory responses, both adaptive and maladaptive, in the lung.

In this issue of the Journal, Villaseñor-Altamirano and colleagues (pp. 1177–1195) performed in-depth profiling of tissue-resident CD8⁺ T cells in mild-moderate chronic obstructive pulmonary disease (COPD) to uncover putative drivers of pathogenic alterations in the lung (2). The presence of CD8⁺ T cells in COPD has been well described in histologic analyses of airways derived from patients (3). These CD8⁺ T cells are mostly localized within lymphoid follicles surrounding the airways that accumulate with disease progression in patients with COPD (4). Preclinical studies have also shown that CD8⁺ T cells are required for the pathologic phenotypes seen in mouse models of emphysema (5). However, these studies preceded the advent of single-cell transcriptomics, which enabled unprecedented capacity to resolve the cellular heterogeneity of COPD lungs through the construction of cellular atlases (6–9). Villaseñor-Altamirano and colleagues specifically focused their study on immune populations that reside in the COPD lung. They performed cellular indexing of transcriptomes and epitopes sequencing along with T cell receptor sequencing of T cells from COPD lungs that beautifully complemented transcriptomics with surface marker and clonotype data at single-cell resolution.

Using this integrated dataset, the authors described a polyclonal expansion of CD8⁺ T cells with terminal differentiation (terminally differentiated effector memory) and resident memory phenotypes in mild-moderate COPD. Ligand-receptor analysis predicted strong interactions between these T cell subsets and other immune subsets (e.g., monocytes, dendritic cells) and important structural cells (alveolar type 2 cells). Of note, IFN-γ stood out as a particularly strong signal that originated from these CD8⁺ T cells to activate monocytes and alveolar type 2 cells in the COPD lungs. This is concordant with recent data from our group and others demonstrating that IFN-primed epithelial progenitors in the alveoli and terminal bronchioles are lost in COPD concurrent with the expansion of IFN-γ⁺ CD8 T cells in the lung (10, 11). Although IFN-γ had previously been implicated in COPD as a potentiator of matrix metalloproteinase expression (12), recent data demonstrated a role for IFN-γ in the direct suppression of lung epithelial progenitor self-renewal (10, 11). These data highlight that IFN-γ is a pleiotropic cytokine that drives pathologic changes in COPD.

What this study left unanswered is which one of these distinct T cell subsets is actually driving tissue pathology. It is difficult to report bad behavior from a neighbor when you do not have the address. Spatial localization of the T cell subsets would shed light on the pathologic features they are driving in COPD (e.g., alveolar destruction, airway metaplasia). This is especially relevant in this study because terminally differentiated effector memory T cells were previously described as largely present in the blood and lymph nodes (13), and their presence in the lung could reflect transit through the pulmonary circulation rather than permanent residency. In another recently published COPD atlas in the Journal (9), the authors used imaging mass spectrometry to resolve the immune subsets present around the terminal bronchioles in COPD that associated the presence of infiltrating CD8⁺ T cells with small airway remodeling.

Finally, data highlighting the presence of CD8⁺ T cells in COPD raise the question of why they are more likely to establish residency in the lungs of patients with COPD. Exacerbations of COPD are often triggered by respiratory pathogens such as viruses (14), which drives an adaptive immune response to expand CD8⁺ T cells in the lung. Normally, the CD8⁺ T cell compartment contracts after the initial infection, with select CD8⁺ T cells establishing residence in the lung (resident memory T cells) that have immunologic memory to respond to future challenges by the same pathogen (1). However, not all smokers who catch a cold develop COPD, so there are likely host susceptibility factors that modify T cell residency in the lung. The authors of this highlighted article have previously shown that haploinsufficiency of Hhip, a gene with variants conferring susceptibility to COPD, induces the accumulation of T cells in the lung (15). Hhip is highly expressed in the lung, and we showed that fibroblast-specific deletion of Hhip potentiated the accumulation of IFN-γ⁺ tissue-resident T cells after respiratory viral infection (11). This suggests that genetic susceptibility driven by common variants could modify host susceptibility to CD8⁺ T cell residency; in other words, certain neighborhoods might just be more attractive to bad neighbors.