CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease

Abstract Background IgG4-related disease (IgG4-RD) is an immune-mediated fibrotic disorder that has been linked to CD4+ cytotoxic T lymphocytes (CD4+CTLs). The effector phenotype of CD4+CTLs, the relevance of both CD8+ cytotoxic T lymphocytes (CD8+CTLs) and of apoptotic cell death remain undefined in IgG4-RD. Objective The goals of this study were to define CD4+CTL heterogeneity, characterize the CD8+CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG4-RD. Methods Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single cell levels and next generation sequencing for the TCR repertoire. Tissues were interrogated using multi-color immunofluorescence. Results were correlated with clinical data. Results We establish that among circulating CD4+CTLs in IgG4-RD, CD27loCD28loCD57hi cells are the dominant effector subset, exhibit marked clonal-expansion and differentially express genes relevant to cytotoxicity, activation and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8+CTLs in disease tissues and clonal-expansion in the blood of effector/memory CD8+ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving non-immune, non-endothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR. Conclusion CD4+CTLs and CD8+CTLs may induce apoptotic cell death in tissues of patients with IgG4-RD with preferential targeting of non-endothelial, non-immune cells of mesenchymal origin. Clinical Implication T cell mediated apoptosis in disease lesions may contribute to the induction of fibrosis in IgG4-RD. Effector CD4+CTLs and CD8+CTLs correlate with disease severity in IgG4-RD.