Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Abstract

Objectives. Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. Methods. Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 (Stim1/2Foxp3), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells fromStim1/2Foxp3mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. Results.Stim1/2Foxp3mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation inStim1/2Foxp3mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells fromStim1/2Foxp3mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4+T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. Conclusions. We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.