Tissue‐Resident Memory CD 8+ T Cells Acting as Mediators of Salivary Gland Damage in a Murine Model of Sjögren's Syndrome

Objective Although a role for CD 4+ T cells in the pathogenesis of Sjögren's syndrome ( SS ) has been documented, the pathogenic significance of CD 8+ T cells is unclear. The aim of this study was to investigate the role of CD 8+ T cells in the development of SS . Methods Flow cytometry and immunofluorescence analyses were utilized to detect T cell infiltration within the labial salivary glands of patients with primary SS . In parallel, p40 −/− CD 25 −/− mice were used as a murine model of SS . In addition, mice with genetic knockout of CD 4, CD 8a, or interferon‐γ ( IFN γ) were crossed with p40 −/− CD 25 −/− mice to study the pathogenic significance of specific lineage subpopulations, including functional salivary gland tests as well as histopathologic and serologic data. A CD 8+ T cell–specific depletion antibody was used in this murine SS model to evaluate its potential as a therapeutic strategy. Results CD 8+ T cells with a tissue‐resident memory phenotype outnumbered CD 4+ T cells in the labial salivary glands of patients with SS , and were primarily colocalized with salivary duct epithelial cells and acinar cells. Furthermore, infiltrating CD 8+ T cells with a CD 69+ CD 103+/− tissue‐resident phenotype and with a significant elevation of IFN γ production were dominant in the submandibular glands of mice in this murine SS model. CD 8a knockout abrogated the development of SS in these mice. Knockout of IFN γ decreased CD 8+ T cell infiltration and gland destruction. More importantly, depletion of CD 8+ T cells fully protected mice against the pathologic manifestations of SS , even after the onset of disease. Conclusion These data reveal the pathogenic significance of CD 8+ T cells in the development and progression of SS in the salivary glands. Treatment directed against CD 8+ T cells may be a rational therapy for the management of SS in human subjects.