CD4 and CD8 cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG-related disease.

Background: IgG-related disease (IgG-RD) is an immune-mediated fibrotic disorder that has been linked to CD4 cytotoxic T lymphocytes (CD4CTLs). The effector phenotype of CD4CTLs and the relevance of both CD8 cytotoxic T lymphocytes (CD8CTLs) and apoptotic cell death remain undefined in IgG-RD.

Objective: We sought to define CD4CTL heterogeneity, characterize the CD8CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG-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 multicolor immunofluorescence. Results were correlated with clinical data.

Results: We establish that among circulating CD4CTLs in IgG-RD, CD27CD28CD57 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 CD8CTLs 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 nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR.

Conclusions: CD4CTLs and CD8CTLs may induce apoptotic cell death in tissues of patients with IgG-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.