GZMK+CD8+ T cells Target A Specific Acinar Cell Type in Sjögren’s Disease

The researchers identified thirty-one unique cell types, including seven previously uncharacterized seromucous acinar cell (SMAC) populations. A specific population, defined as PRR4+CST3+WFDC2- cells, was found to be the primary target of autoimmune destruction in SjD, showing significant reduction in affected patients. The study demonstrates that GZMK+ CD8+ exhausted T cells (Tex) are highly enriched in the glandular infiltrate and physically associate with these vulnerable epithelial cells. Unlike conventional cytotoxic T cells that secrete GZMB, these GZMK+ cells perform a unique, non-apoptotic effector function: they secrete GZMK, which is taken up by epithelial cells, where it triggers the relocalization of mitochondrial DNA into the cytosol. This process activates innate immune sensing pathways, specifically the IRF/Type I interferon response, thereby bridging adaptive immune targeting with chronic inflammation.

These findings provide a mechanistic link between adaptive immune infiltration and the characteristic Type I interferon signature observed in SjD tissues. By identifying a specific, vulnerable SMAC population and demonstrating how GZMK+ T cells selectively trigger innate signaling rather than simple necrotic cell death, this work shifts the focus of SjD pathology toward the interaction between tissue-resident T cells and the epithelial cells they modulate. This insight offers a potential new therapeutic target for preserving glandular function before irreversible tissue damage occurs.