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 3

CD226 enhances the activation of CD57+ Tem cells.

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CD226 enhances the activation of CD57+ Tem cells. (A) DEG analysis betwe...
(A) DEG analysis between the CD57+ Tem cell cluster and the Temra CD8+ T cell cluster from the scRNA-seq data. (B and C) Expression of ITGA4 and ITGB1 in CD57+ Tem and Temra CD8+ T cells from patients with SSc-ILD assessed by bulk RNA-seq (n = 5) and flow cytometry (n = 6). Wilcoxon test shown. (D) Expression of ITGA4, ITGB1, ZNF683, CD226, and TIGIT in CD8+ T cell clusters. (E) Representative expression of CD226 and TIGIT on CD57+ Tem cells and Temra CD8+ T cells by flow cytometry. (F and G) CD226 and TIGIT expression on CD57+ Tem cells and Temra CD8+ T cells by flow cytometry. The samples from 11 HCs (F) and 6 patients with SSc-ILD (G) were used. P values in F and G were determined by Wilcoxon test. (H) Validation of CD226 and TIGIT expression in cohort 2 (SSc-ILD, n = 41). P values were determined by Wilcoxon test. (I) Protocol scheme of the cytotoxicity assay to assess the effect of CD155 on CD57+ Tem and Temra CD8+ T cells. (J) Proportion of annexin+ L cells with or without CD155 after coculturing with CD8+ T cell subsets. CD57+ Tem cells and Temra CD8+ T cells were collected from 8 HC donors. P values were determined by Wilcoxon test.