IFN-γ-producing T1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren's disease.

Sjögren's disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (T) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of T cells depend on store-operated Ca entry (SOCE), which is mediated by ORAI1 Ca channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3 T cell-specific deletion of and develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (T1) and interferon (IFN) signaling. CD4 T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ-dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4 T cell-induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4 T cells from patients with SjD, which indicate enhanced T1 but reduced memory T cell function. Together, our study provides evidence for a critical role of dysfunctional T cells and IFN-γ-producing T1 cells in the pathogenesis of SjD.