Granzyme K associates with inflammatory immune programs and B-cell dysregulation in systemic lupus erythematosus
Abstract
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.
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BibTeX
@article{pu2026granzyme,
title = {{Granzyme K associates with inflammatory immune programs and B-cell dysregulation in systemic lupus erythematosus}},
author = {Yunjing Pu and Zhongyu Chen and Peihui Yang and Qinghuan Zhu and Haojun Long and Yali Zhou and Danqi Deng},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1934348},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1934348},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Granzyme K associates with inflammatory immune programs and B-cell dysregulation in systemic lupus erythematosus
AU - Yunjing Pu
AU - Zhongyu Chen
AU - Peihui Yang
AU - Qinghuan Zhu
AU - Haojun Long
AU - Yali Zhou
AU - Danqi Deng
PY - 2026
DA - 2026/11/04
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1934348
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1934348
AB - 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.
SN - 1664-3224
ER -