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 patients with lupus were analysed. 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 were evaluated ex vivo. FINDINGS: Our scRNA-seq analysis showed an accumulation of effector memory (EM) CD8(+) T cell subsets that expressed low levels of the IL7 receptor gene (IL7R(low)) but high levels of effector molecule genes, including GZMB, GZMK, PRF1, and GNLY, in the peripheral blood and kidneys of patients with lupus. 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 IL7R(low) CD8(+) T cell subsets correlated with type I IFN gene signature in the peripheral blood of paediatric and adult patients with lupus. IL7R(low) EM CD8(+) T cells induced neutrophil extracellular trap (NET), a key inflammatory pathway in lupus pathogenesis, dependently of TNF-α and IFN-γ. INTERPRETATION: Our study provides insights into lupus pathogenesis by demonstrating the clinical and biological implications of cytotoxic and inflammatory IL7R(low) EM CD8(+) T cell accumulation in lupus. This raises the prospect of therapeutic targets aimed at such CD8(+) T cells. FUNDING: Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00249,430) as well as by the National Institutes of Health (1R01AR082203 and 2RF1AG056728 to IK, 5T32AR007107 to LO and JPY) and the Rheumatology Research Foundation (to IK).