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Implications of Cytotoxic and Inflammatory Human IL-7 Receptor Alpha Low Effector Memory CD8+ T Cells in Lupus
34 Pages Posted: 11 Mar 2025
More...Abstract
Background: This study aims to interrogate the implications of CD8+ T cells in lupus by examining CD8+ T cell heterogeneity and assessing the significance of this heterogeneity in promoting inflammation and tissue damage.
Methods: Our own and publicly available RNA-seq and microarray data from the peripheral blood and kidney tissues of lupus patients were analyzed. Imaging Mass Cytometry (IMC) analysis of immune cells was conducted in lupus and normal kidney tissues. The effects of CD8+ T cell subsets on neutrophils and monocytes were evaluated ex vivo.
Findings: 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 genes, including GZMB, GZMK, PRF1, and GNLY, in the peripheral blood and kidneys of lupus patients. CD8+ T cell infiltrations and cytotoxic molecule expression in lupus kidney tissues were associated with treatment outcomes, as determined by IMC. The gene signatures of IL7Rlow CD8+ T cell subsets correlated with type I IFN gene signature in the peripheral blood of pediatric and adult lupus patients. IL7Rlow EM CD8+ T cells induced neutrophil extracellular trap (NET) and augmented lupus immune complex-mediated monocyte activation, key inflammatory pathways in lupus pathogenesis, dependently of TNF-a and IFN-g.
Interpretation: Our study provides unique insights into lupus pathogenesis by demonstrating the clinical and biological implications of cytotoxic and inflammatory IL7Rlow EM CD8+ T cell expansion in lupus. This raises the prospect of therapeutic targets aimed at such CD8+ T cells.
Keywords: CD8+ T cells, Lupus, IL7 receptor, Neutrophils, and Monocytes
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