Interleukin-7 Enhances the Th1 Response to Promote the Development of Sjogren's Syndrome-like Autoimmune Exocrinopathy in Mice

Objective. Although elevated interleukin-7 (IL-7) levels have been reported in patients with primary Sjogren's syndrome (SS), the role of IL-7 in this disease remains unclear. We undertook this study to characterize the previously unexplored role of IL-7 in the development and onset of primary SS using the C57BL/6. NOD-Aec1Aec2 (B6.NOD-Aec) mouse model, which recapitulates human primary SS. Methods. For gain-of-function studies, recombinant IL-7 or control phosphate buffered saline was injected intraperitoneally (IP) into 12-week-old B6.NOD-Aec mice for 8 weeks. For loss-of-function studies, anti-IL-7 receptor alpha-chain (anti-IL-7R alpha) antibody or its isotype control IgG was administered IP into 16-week-old B6.NOD-Aec mice. Salivary flow measurement, histologic and flow cytometric analysis of salivary glands, and serum antinuclear antibody assay were performed to assess various disease parameters. Results. Administration of exogenous IL-7 accelerated the development of primary SS, whereas blockade of IL-7R alpha signaling almost completely abolished the development of primary SS, based on salivary gland inflammation and apoptosis, autoantibody production, and secretory dysfunction. IL-7 positively regulated interferon-gamma (IFN gamma)-producing Th1 and CD8+ T cells in the salivary glands without affecting IL-17. Moreover, IL-7 enhanced the expression of CXCR3 ligands in a T cell- and IFN gamma-dependent manner. Accordingly, IFN gamma induced a human salivary gland epithelial cell line to produce CXCR3 ligands. IL-7 also increased the level of tumor necrosis factor alpha, another Th1-associated cytokine that can facilitate tissue destruction and inflammation. Conclusion. IL-7 plays a pivotal pathogenic role in SS, which is underpinned by an enhanced Th1 response and IFN gamma/CXCR3 ligand-mediated lymphocyte infiltration of target organs. These results suggest that targeting the IL-7 pathway may be a potential future strategy for preventing and treating SS.