Work

IFN-γ–producing T H 1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren’s disease

Year: 2024

Type: article

Abstract: 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 reg ) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of T reg cells depend on store-operated Ca 2+ entry (SOCE), which is mediated by ORAI1 Ca 2+ channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3 + T reg 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 (T H 1) 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 T H 1 but reduced memory T reg cell function. Together, our study provides evidence for a critical role of dysfunctional T reg cells and IFN-γ–producing T H 1 cells in the pathogenesis of SjD.

Source: Science Translational Medicine

DOI: 10.1126/scitranslmed.ado4856