A CD57+CD8+ T cell subset links T cell cytotoxicity to fibrotic lung disease in systemic sclerosis
Takanori Sasaki, Ye Cao, John M. Sowerby, Kazuhiko Higashioka, Kathryne E. Marks, Mehreen Elahee, Mari Kamiya, Paul F. Dellaripa, Richard I. Ainsworth, Kimberly E. Taylor, Nunzio Bottini, Paul Wolters, Edy Y. Kim, Francesco Boin, Deepak A. Rao
Takanori Sasaki, Ye Cao, John M. Sowerby, Kazuhiko Higashioka, Kathryne E. Marks, Mehreen Elahee, Mari Kamiya, Paul F. Dellaripa, Richard I. Ainsworth, Kimberly E. Taylor, Nunzio Bottini, Paul Wolters, Edy Y. Kim, Francesco Boin, Deepak A. Rao
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Research Article Autoimmunity Immunology

A CD57+CD8+ T cell subset links T cell cytotoxicity to fibrotic lung disease in systemic sclerosis

Abstract

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc); however, the immunopathologic mechanisms driving lung disease in SSc are unclear. T cells have been implicated as a likely driver of lung injury in SSc. Here, we evaluated T cells in the blood of patients with SSc-ILD and identified a specific population of cytotoxic CD8+ T cells that was expanded in patients with SSc-ILD. Cytotoxic effector memory CD8+ T cells marked by CD57 expression were preferentially expanded in patients with SSc-ILD compared with patients with SSc but no ILD and control individuals and showed prominent clonal expansion. These CD57+ T effector memory (Tem) cells differed from T effector memory cells reexpressing CD45RA (Temra) transcriptomically and functionally, with cytotoxic function that was enhanced by CD155 engagement of the costimulatory receptor CD226. We performed immunostaining of lung tissue samples obtained from independent patients with SSc-ILD (biopsy or explant) and confirmed the presence of CD57+ Tem cells. In parallel, we analyzed publicly available lung scRNA-seq datasets from multiple ILD cohorts and identified endothelial cells as a likely source of CD155 for the activation of CD57+ cytotoxic T cells. Together, the results implicate a CD57+ cytotoxic CD8+ T cell population as a potential mediator of lung injury in SSc-ILD.

Authors

Takanori Sasaki, Ye Cao, John M. Sowerby, Kazuhiko Higashioka, Kathryne E. Marks, Mehreen Elahee, Mari Kamiya, Paul F. Dellaripa, Richard I. Ainsworth, Kimberly E. Taylor, Nunzio Bottini, Paul Wolters, Edy Y. Kim, Francesco Boin, Deepak A. Rao

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Figure 4

CD57+ Tem cells are expanded in SSc-ILD lung tissues.

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CD57+ Tem cells are expanded in SSc-ILD lung tissues. (A) UMAP clusterin...
(A) UMAP clustering of T cells in lung tissue scRNA-seq data from 4 SSc-ILD donors (24). (B) Gene expression of the T cell clusters from A. (C) UMAP clustering of T cells in lung tissue scRNA-seq data generated from 66 patients with ILD and 48 control donors (25). (D) CNA of CD8+ T cells from the scRNA-seq data, adjusting for age and sex. Red indicates cell neighborhoods enriched in ILD samples. (E) Gene expression of the CD8+ clusters in the scRNA-seq data in C. (F) Representative images of CD57+, CD8+, and CD45RA+ staining of SSc-ILD lung tissue. Scale bars: 500 μm and 20 μm. (G) Quantification of CD57+CD45RA–CD8+ in tissue stainings. (HCs: n = 4, SSc-ILD: n = 11). P value was determined by Mann-Whitney U test. Box plots represent median and interquartile range (25th-75th percentiles), with whiskers indicating minimum and maximum values.