Interleukin‐7 Enhances the Th1 Response to Promote the Development of Sjögren's Syndrome–like Autoimmune Exocrinopathy in Mice

Abstract

Objective Although elevated IL-7 levels were reported in patients with primary Sjӧgren’s syndrome (pSjS), the role of IL-7 in this disease remains unclear. Here we characterized the previously unexplored role of IL-7 in the development and onset of pSjS using C57BL/6.NOD-Aec1Aec2 (B6.NOD-Aec) mouse model that recapitulates human pSjS. Methods For gain-of-function studies, recombinant IL-7 or control PBS was injected intraperitoneally (i.p.) into 12-week old B6.NOD-Aec mice for 8 weeks. For loss-of-function studies, neutralizing anti-IL-7 receptor antibody or its isotype control IgG was administered i.p. into 16-week old B6.NOD-Aec mice. Salivary flow measurement, histological 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, whereas blockade of IL-7 receptor signaling almost completely abolished the development of pSjS, based on salivary gland inflammation and apoptosis, autoantibody production and secretory dysfunction. IL-7 positively regulated IFN-γ-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-γ-dependent fashion. Accordingly, IFN-γ induced a human salivary gland epithelial cell line to produce CXCR3 ligands. IL-7 also increased the level of TNF-α, another Th1-associated cytokine that can facilitate tissue destruction and inflammation. Conclusion IL-7 plays a pivotal pathogenic role in SjS, which is underpinned by an enhanced Th1 response and IFN-γ-CXCR3 ligand-mediated lymphocyte infiltration of target organs. These results suggest that targeting IL-7 pathway may be a potential future strategy to prevent and treat SjS.

Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss

“…We found that IL-7 induced expansion of Th1/a2b1 + cells (50% of Th1 express a2b1 integrin versus 80% of Th17 that express a2b1) in the bone marrow, and the blocking anti-a2b1 integrin mAb reduced their numbers (26 versus 40% reduction of Th17 cells; data not shown). These results are in agreement with previous studies showing that IL-7 can also regulate Th1 cells (12,52), which also express a2b1 integrin, and collagen costimulates the production of IFN-g (53). In contrast, we have not detected Th1/Th17 cells in the bone marrow and these cells were not induced upon treatment with IL-7 (data not shown).…”

Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen

“…Furthermore, IL-7 induces proliferation of naive and memory T cells (15) and enhances effector T cell responses, preferentially T helper 1 (Th1) and Th17 responses (16-18). These functional effects of IL-7 on T cells make IL-7 a critical enhancer of protective immunity, as well as of autoimmunity and inflammation (16,17,19,20).In the case of bacterial infections, gastric tissue biopsy specimens from patients infected with Helicobacter pylori (21) or mice infected with Mycobacterium tuberculosis have increased expression of . In addition, administration of exogenous IL-7 enhanced the survival of M. tuberculosis-infected mice (23).…”

“…Moreover, IL-7 supports CD4 ϩ lymphoid tissue inducer (LTi) cell survival and function (14). Furthermore, IL-7 induces proliferation of naive and memory T cells (15) and enhances effector T cell responses, preferentially T helper 1 (Th1) and Th17 responses (16)(17)(18). These functional effects of IL-7 on T cells make IL-7 a critical enhancer of protective immunity, as well as of autoimmunity and inflammation (16,17,19,20).…”

Innate Immune Signaling Induces IL-7 Production, Early Inflammatory Responses, and Sjögren's-Like Dacryoadenitis in C57BL/6 Mice

“…12 Moreover, we have reported that endogenous and exogenous IL-7 enhances Th1 responses and plays an essential role in the development and onset of SS-like exocrinopathy of salivary glands. 13 These findings provide additional evidence for the pathologic consequences of excessive IL-7 production induced by innate immune signaling 14 that can facilitate the pathogenesis of development and onset of multiple autoimmune disorders, mainly by enhancing Th1 and T cytotoxic 1 (Tc1) immune responses in the target tissues. [15][16][17][18] The lacrimal gland (LAC) is a primary target organ affected by SS.…”

“…To determine whether similar events are induced by poly I:C in the LAC, we pretreated C57BL/6 mice with an anti-IL-7Ra antibody, which competitively inhibits IL-7 binding to IL7Ra, 12,13 or its isotype control IgG before IP administration of poly I:C. Poly I:C treatment induced a considerable increase in the expression of all three CXCR3 ligands, CXCL9, 10, and 11, in the LAC, and this increase was dramatically reduced by anti-IL7Ra treatment ( Fig. 2A).…”