Abstract
Type I interferon (IFN-I) is highly prevalent in autoimmune disorders and is intricately involved in disease pathogenesis, including Sjögren's disease (SjD), also known as Sjögren's syndrome. Although the T follicular helper (Tfh) cell response has been shown to drive SjD development in a mouse model of experimental Sjögren's syndrome (ESS), the connection between IFN-I and the Tfh cell response remains unclear. As the activation of stimulator of interferon genes (STING) induces IFN-I production, we first demonstrated that mice deficient in STING or IFN-I signaling presented diminished Tfh cells and were completely resistant to ESS development. However, the STING-IFN-I axis does not directly influence Tfh cell differentiation. Instead, IFN-I signaling in B cells was essential for mounting Tfh cell responses, as evidenced in Cd19CreIfnar1flox mice, which also showed resistance to ESS development. Mechanistic analyses revealed that IFN-I drove CXCR5 expression in innate-like marginal zone B cells via the MEKK3-OCT2 axis, facilitating their migration into the follicular area. Additionally, IFN-I promoted interleukin-6 production in B cells via the MEKK3-ERK5 axis, resulting in hyperactive Tfh cell responses. In SjD patients, STING activation was predominantly observed in circulating CD14+ monocytes and was positively correlated with disease activity and effector T-cell responses. Pharmaceutical inhibition of either STING or IFNAR1 yielded moderate improvements in ESS mice with chronic inflammation, but combination therapy markedly improved outcomes and led to signs of disease remission. Our findings elucidate a novel mechanism by which IFN-I bridges innate and Tfh cell responses, suggesting new therapeutic avenues for SjD and related autoimmune disorders.