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 2

Developmental and clonal relationship between CD57+ Tem cells and Temra CD8+ T cells.

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Developmental and clonal relationship between CD57+ Tem cells and Temra ...
(A)Bulk RNA-seq sorting strategy for CD8+ T cell populations in this study: naive CD8+ T cells (CD57–CD27+CCR7+CD45RA+CD56–), CD57– Tem cells (CD57–CD27+CCR7–CD45RA–CD56–), CD57+ Tem cells (CD57+CD27–CCR7–CD45RA–CD56–), and Temra CD8+ T cells (CD57+CD27–CCR7–CD45RA+CD56–) from 5 SSc-ILD donors were sorted. (B) PCA plots of naive CD8+ T cells, CD57– Tem cells, CD57+ Tem cells, and Temra CD8+ T cells. (C) Heatmap of the expression of selected genes in bulk RNA-seq data from T cell subsets. (D) Gene module scores in CD8+ T cells in the scRNA-seq data. (E) Pseudotime analysis of CD8+ T cells in the scRNA-seq dataset. (F) Expanded TCR clones depicted onto the transcriptionally defined UMAP visualization. (G) Proportions of top 50 clonotypes of total clonotypes in naive, Tcm, CD57– Tem, CD57+ Tem, and Temra CD8+ T cells.