Granzyme K associates with inflammatory immune programs and B-cell dysregulation in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by systemic immune activation and multi-organ inflammation. Granzyme K (GZMK), a serine protease predominantly expressed by CD8 + T cells and natural killer cells, has emerging non-cytotoxic inflammatory functions, but its relevance to SLE remains incompletely defined. In this study, we conducted investigations using plasma and tissue analyses, single-cell RNA sequencing, proteomics, multiplex immunofluorescence, an animal model, and primary human B cell experiments. Plasma GZMK was increased in patients with SLE and was associated with clinical disease activity. Integrated multi-tissue single cell analysis identified preferential GZMK enrichment in CD8 + effector memory T (Tem) cells and a higher relative abundance of this compartment in SLE, while proteomic profiling and multiplex immunofluorescence provided protein and tissue level evidence for a GZMK-enriched CD8 + memory T cell population. Cell–cell communication analysis suggested enhanced predicted communication between Tem and B lineage cells, and circulating GZMK was further associated with a plasma cell-like population. In two murine models, PPACK, which can inhibit GZMK catalytic activity but is not GZMK selective, attenuated lupus associated inflammatory phenotypes and partially normalized altered splenic B cell composition. In vitro experiments showed that active recombinant GZMK augmented plasma-cell-associated phenotypic and transcriptional responses under B cell expansion conditions. Collectively, these findings identify circulating GZMK as an independent correlate of SLE clinical activity and characterize a recurrent GZMK-enriched CD8 + memory/Tem cell program across peripheral blood and affected tissues that is associated with B-cell dysregulation and plasma-cell-related immune abnormalities.