IFN-γ-producing TH1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren's disease.

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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 (Treg) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of Treg cells depend on store-operated Ca2+ entry (SOCE), which is mediated by ORAI1 Ca2+ channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3+ Treg cell-specific deletion of Stim1 and Stim2 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 (TH1) 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 TH1 but reduced memory Treg cell function. Together, our study provides evidence for a critical role of dysfunctional Treg cells and IFN-γ-producing TH1 cells in the pathogenesis of SjD.