Cytotoxic CD161(−)CD8(+) T(EMRA) cells contribute to the pathogenesis of systemic lupus erythematosus

BACKGROUND: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease affecting multiple organs and tissues with high cellular heterogeneity. CD8(+) T cell activity is involved in the SLE pathogenesis. However, the cellular heterogeneity and the underlying mechanisms of CD8(+) T cells in SLE remain to be identified. METHODS: Single-cell RNA sequencing (scRNA-seq) of PBMCs from a SLE family pedigree (including 3 HCs and 2 SLE patients) was performed to identify the SLE-associated CD8(+) T cell subsets. Flow cytometry analysis of a SLE cohort (including 23 HCs and 33 SLE patients), qPCR analysis of another SLE cohort (including 30 HCs and 25 SLE patients) and public scRNA-seq datasets of autoimmune diseases were employed to validate the finding. Whole-exome sequencing (WES) of this SLE family pedigree was used to investigate the genetic basis in dysregulation of CD8(+) T cell subsets identified in this study. Co-culture experiments were performed to analyze the activity of CD8(+) T cells. FINDINGS: We elucidated the cellular heterogeneity of SLE and identified a new highly cytotoxic CD8(+) T cell subset, CD161(−)CD8(+) T(EMRA) cell subpopulation, which was remarkably increased in SLE patients. Meanwhile, we discovered a close correlation between mutation of DTHD1 and the abnormal accumulation of CD161(−)CD8(+) T(EMRA) cells in SLE. DTHD1 interacted with MYD88 to suppress its activity in T cells and DTHD1 mutation promoted MYD88-dependent pathway and subsequently increased the proliferation and cytotoxicity of CD161(−)CD8(+) T(EMRA) cells. Furthermore, the differentially expressed genes in CD161(−)CD8(+) T(EMRA) cells displayed a strong out-of-sample prediction for case–control status of SLE. INTERPRETATION: This study identified DTHD1-associated expansion of CD161(−)CD8(+) T(EMRA) cell subpopulation is critical for SLE. Our study highlights genetic association and cellular heterogeneity of SLE pathogenesis and provides a mechanistical insight into the diagnosis and treatment of SLE. FUNDINGS: Stated in the Acknowledgements section of the manuscript.