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Multi temperal single-cell profiling decodes cross-talk of γδ17 T cells and neutrophils in radiation pneumonitis

ABSTRACT: Radiation pneumonitis (RP) is a common and fatal complication in thoracic radiation therapy. The immune microenvironment plays an important role in the RP development. However, the full scope of radiation immune changes over time remains unclear. In this study, a murine model of RP was established, and distinct early (10 days) and late phases (100 days) were defined. We conducted single-cell RNA sequencing and related RNA-seq and proteomics to explore the underlying mechanisms of persistent inflammation during RP. By examining the immunological effects of RP over time at the single-cell level, we shed light on its dynamic immunological effects of RP over time at single-cell resolution and provided potential therapeutic targets for clinical interventions.

ORGANISM(S): Mus musculus

PROVIDER: GSE236049 | GEO | 2024/05/24

REPOSITORIES: GEO

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Project description:Rationale: Fibrotic hypersensitivity pneumonitis is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in fibrotic hypersensitivity pneumonitis in single-cell resolution. Methods: Single-cell 5’ RNA sequencing was conducted on peripheral blood mononuclear cells and bronchoalveolar lavage cells obtained from 45 patients with fibrotic hypersensitivity pneumonitis, 63 idiopathic pulmonary fibrosis, 4 non-fibrotic hypersensitivity pneumonitis, and 36 healthy controls in the United States and Mexico. Analyses included differential gene expression (Seurat), transcription factor activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3/Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and controls and 88,336 bronchoalveolar lavage cells from 19 patients were profiled. Compared to controls, fibrotic hypersensitivity pneumonitis has elevated classical monocytes (adjusted-p=2.5e-3) and are enriched in CCL3hi/CCL4hi and S100Ahi classical monocytes (adjusted-p<2.2e-16). Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. Compared to both controls and idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis patient cells are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit transcription factor activities indicative of TGFb and TNFa/NFkB pathways. These results are publicly available at https://ildimmunecellatlas.org. Conclusions: Single-cell transcriptomics of fibrotic hypersensitivity pneumonitis patients uncovered novel immune perturbations, including previously undescribed increases in GZMhi cytotoxic CD4+ and CD8+ T cells – reflecting this disease’s unique inflammatory T-cell driven nature – as well as increased S100Ahi and CCL3hi/CCL4hi classical monocytes also observed in idiopathic pulmonary fibrosis. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

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Multi temperal single-cell profiling decodes cross-talk of γδ17 T cells and neutrophils in radiation pneumonitis

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