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

Yin Hu Wang, Wenyi Li, Maxwell McDermott, Ga Yeon Son, George Maiti, Fang Zhou, Anthony Y. Tao, Dimitrius Raphael, Andre L. Moreira, Boheng Shen, Martin Vaeth, Bettina Nadorp, Shukti Chakravarti, Rodrigo S. Lacruz, Stefan Feske

Research output: Contribution to journalArticlepeer-review

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 (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.

Original languageEnglish (US)
Article numbereado4856
JournalScience Translational Medicine
Volume16
Issue number778
DOIs
StatePublished - Dec 18 2024

ASJC Scopus subject areas

  • General Medicine

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