The role of airway tissue-resident memory T Cells in severe asthma

Abstract

The growing realisation that severe asthma encompasses a collection of clinical phenotypes and endotypes, plus the variable response to current asthma therapies suggest underlying pathophysiological heterogeneity and complex immune molecular pathways.

T cells are critical orchestrators of airway inflammation. However, the role of tissue-resident memory T (TRM) cells, localised to sites of inflammation in the airway epithelium, in the pathogenesis of severe asthma remains unknown. Therefore, this thesis aims to investigate the molecular heterogeneity of airway CD4+ and CD8+ TRM cells in severe asthma pathogenesis and extend this characterisation to the underlying clinical phenotypic nature of severe asthma compared to mild asthma.

In the first section of this thesis, I undertook extensive clinical phenotypic characterisation of participants with difficult/severe and mild asthma (Chapter 3). Subsequent separate K-means clustering analysis of the difficult/severe and mild asthma cohorts identified 6 clinically relevant difficult/severe asthma clusters and 2 mild asthma clusters, reflecting severe disease heterogeneity (Chapter 4).

For the second section of this thesis, bronchoalveolar (BAL) fluid samples collected from a proportion of severe and mild asthma participants were immunophenotyped using flow cytometry. This analysis suggested that CD103+CD4+ TRM and CD103+CD8+ TRM cells represented the dominant population in asthma. Subsequent bulk and single-cell RNA-seq of BAL memory CD4+ (Chapter 5) and CD8+ (Chapter 6) T cell populations were completed to investigate the molecular profiles of these cells in relation to asthma severity. The transcriptional profiling of BAL CD4+ T cells highlighted a novel population of cytotoxic CD103+CD4+ TRM cells enriched for transcripts linked to TCR activation, TH1-like cytotoxicity and pro-inflammatory molecular features, which was associated with increasing asthma severity in the male adult-onset severe asthma phenotype. In contrast, the transcriptional profiling of BAL CD8+ T cells revealed 9 transcriptionally distinct putative airway CD103+CD8+ TRM cell states across the spectrum of asthma severity, thus highlighting significant molecular heterogeneity. Strikingly, 3 airway CD8+ TRM cell states were unique to severe asthma and appeared to be highly proliferative with enhanced cytotoxicity, glucocorticoid insensitivity and pro-inflammatory molecular properties. Such superior functional properties of cytotoxic CD103+CD4+ TRM and CD103+CD8+ TRM cells suggest their role as key drivers of persistent airway inflammation, remodelling and glucocorticoid insensitivity in severe asthma.

In conclusion, these novel findings indicate the need to look beyond the traditional T2 model of severe asthma to better understand disease heterogeneity. Future work will aim towards completing functional studies in vivo to better understand the molecular role of airway CD4+ and CD8+ TRM cell populations and their interactions in severe asthma.

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Identifiers

ORCID for Heena Mohanbhai Mistry: orcid.org/0000-0003-2679-1122

ORCID for Ramesh Kurukulaaratchy: orcid.org/0000-0002-1588-2400

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