Implication of inflammatory cytotoxic IL-7 receptor alpha low effector memory CD8+ T cells that promote innate immunity in lupus.

Objective. The pathogenesis of systemic lupus erythematosus (SLE or lupus) involves multiple immune components although the role for CD8+ T cells, which potently induce inflammation and tissue damage, is less known in lupus. The aim of this study was to interrogate the implications of CD8+ T cells in lupus by examining heterogeneity of CD8+ T cells in the kidneys and peripheral blood of lupus patients and assessing functional significance of such heterogeneity in promoting inflammation and tissue damage. Methods. An integrated dataset of our own and publicly available scRNA-seq data from the peripheral blood and kidney tissue samples of lupus patients was analyzed followed by validating these findings with an independent scRNA-seq dataset of the peripheral blood of lupus patients and Imaging Mass Cytometry analysis of lupus and normal kidney tissue samples. The interface of CD8+ T cell subsets with neutrophils and monocytes was assessed using cell culture, qPCR, ELISA, flow cytometry, and immunofluorescent staining. Results. The results of our scRNA-seq analysis showed an expansion of effector memory (EM) CD8+ T cell subsets that expressed low levels of the IL7 receptor gene (IL7Rlow) but high levels of cytotoxicity related genes, including GZMB, GZMH, GZMK, PRF1, and GNLY, in the peripheral blood and kidneys of lupus patients. Patients with lupus nephritis who progressed to renal failure (or end stage renal disease) had increased numbers and expression levels of CD8+ T cells and cytotoxic molecules, respectively, at the protein level in the kidney tissue as compared to lupus patients who achieved remission of lupus nephritis, supporting the involvement of such cells and molecules in impairing renal function. The gene signatures of IL7Rlow CD8+ T cell subsets correlated with type I IFN gene signature in the peripheral blood of both pediatric and adult lupus patients. Our ex vivo functional study showed that IL7Rlow EM CD8+ T cells potently induced neutrophil extracellular trap (NET) formation and augmented lupus immune complex mediated monocyte activation, supporting the functional implication of the expanded IL7Rlow EM CD8+ T cells in promoting inflammation and tissue damage. Conclusion. Our findings advance our understanding of the implication of CD8+ T cells, especially IL7Rlow EM CD8+ T cells expressing cytotoxic molecules, in sustaining inflammation and tissue damage in lupus.