Granzyme A-Producing Type 1 Innate Lymphoid Cells Restore Salivary Secretion in the Aged Submandibular Gland

We analyzed mice across aging stages, measuring saliva output and histology, and performed site-specific single-cell RNA sequencing around lymphoid clusters to infer immune–epithelial interactions, validated in coculture and in vivo depletion models. Saliva production was preserved or slightly increased in early aging, coinciding with lymphoid cluster formation enriched in Gzma⁺ ILC1s predicted to interact with epithelial cells via the Gzma–Pard3 axis, which enhanced Aqp5 expression in vitro.

Depletion of ILC1s in aged mice reduced saliva output, demonstrating that ILC1-derived GZMA supports epithelial secretory capacity. Thus, aging salivary glands accumulate ILC1s that sustain epithelial function through a GZMA-dependent pathway, maintaining secretion and identifying the GZMA–Pard3 axis as a potential target to preserve gland function and prevent xerostomia-related disorders.