Clonally Expanded CD8+ T Cell-Derived IFNγ Drives Sjögren's Dacryoadenitis Pathogenesis

Sjögren's disease (SjD) is a chronic, progressive autoimmune disorder primarily targeting exocrine glands, leading to symptoms like dry eyes and mouth. Dacryoadenitis, inflammation of the lacrimal glands, is a common manifestation of SjD, yet its precise pathogenic mechanisms remain poorly understood. Current treatments often manage symptoms but do not fully address the underlying immune dysregulation. Elucidating the specific immune cell subsets and molecular factors driving lacrimal gland pathology is crucial for developing targeted therapies beyond symptomatic relief. This study aimed to identify the key cellular and molecular drivers within the lacrimal gland's immune microenvironment.

Researchers utilized Aire-/- mice, a well-established preclinical model for SjD-related dacryoadenitis, to investigate the immune landscape of the lacrimal glands. Lacrimal gland-infiltrating immune cells were comprehensively profiled using single-cell RNA sequencing and validated by flow cytometry. The T-cell receptor (TCR) repertoire of lacrimal gland T cells was further characterized via single-cell TCR sequencing to identify clonal expansions. To directly assess the role of IFNγ, Ifng-/-Aire-/- mice were generated, allowing for evaluation of IFNγ knockout on disease progression. Additionally, CD8+ T cell deletion was performed to confirm the cellular source. Immunologic profiles and histopathological changes, including inflammatory infiltration and acinar atrophy, were meticulously assessed in Aire-/- mice with and without these genetic interventions.

Single-cell profiling revealed a distinct, clonally expanded population of CCL5+CD8+ memory T cells within the lacrimal glands of Aire-/- mice. These cells exhibited high expression of cytotoxic effector molecules and were found in close spatial proximity to acinar cells, suggesting direct involvement in tissue damage. Further analysis demonstrated that IFNγ secreted by these CCL5+CD8+ memory T cells acts on multiple cell types within the lacrimal gland, leading to the upregulation of various costimulatory molecules and chemokines, thereby perpetuating the inflammatory cascade. > Notably, both CD8+ T cell deletion and IFNγ knockout in Aire-/- mice resulted in a marked attenuation of inflammatory infiltration and significantly reduced acinar atrophy within the lacrimal glands. These findings strongly implicate IFNγ as a central mediator of SjD-related dacryoadenitis pathogenesis, originating from a specific, clonally expanded CD8+ T cell subset.