Upregulated IL-7 Receptor Expression on Colitogenic Memory CD4+ T Cells May Participate in the Development and Persistence of Chronic Colitis

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
The Journal of Immunology (Impact Factor: 4.92). 02/2011; 186(4):2623-32. DOI: 10.4049/jimmunol.1000057
Source: PubMed


We have previously demonstrated that IL-7 is essential for the persistence of colitis as a survival factor of colitogenic IL-7Rα-expressing memory CD4(+) T cells. Because IL-7Rα is broadly expressed on various immune cells, it is possible that the persistence of colitogenic CD4(+) T cells is affected by other IL-7Rα-expressing non-T cells. To test this hypothesis, we conducted two adoptive transfer colitis experiments using IL-7Rα(-/-) CD4(+)CD25(-) donor cells and IL-7Rα(-/-) × RAG-2(-/-) recipient mice, respectively. First, IL-7Rα expression on colitic lamina propria (LP) CD4(+) T cells was significantly higher than on normal LP CD4(+) T cells, whereas expression on other colitic LP immune cells, (e.g., NK cells, macrophages, myeloid dendritic cells) was conversely lower than that of paired LP cells in normal mice, resulting in predominantly higher expression of IL-7Rα on colitogenic LP CD4(+) cells, which allows them to exclusively use IL-7. Furthermore, RAG-2(-/-) mice transferred with IL-7Rα(-/-) CD4(+)CD25(-) T cells did not develop colitis, although LP CD4(+) T cells from mice transferred with IL-7Rα(-/-) CD4(+)CD25(-) T cells were differentiated to CD4(+)CD44(high)CD62L(-) effector-memory T cells. Finally, IL-7Rα(-/-) × RAG-2(-/-) mice transferred with CD4(+)CD25(-) T cells developed colitis similar to RAG-2(-/-) mice transferred with CD4(+)CD25(-) T cells. These results suggest that IL-7Rα expression on colitogenic CD4(+) T cells, but not on other cells, is essential for the development of chronic colitis. Therefore, therapeutic approaches targeting the IL-7/IL-7R signaling pathway in colitogenic CD4(+) T cells may be feasible for the treatment of inflammatory bowel diseases.

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    • "In UC patients, IL-7 protein expression is significantly upregulated and exerts its optimal effects in maintaining long-lived memory CD4+ T cells in colonic mucosa.32 IL-7 appears to mediate the persistence of chronic colitis through the IL-7Rα chain expressed specifically on CD4+ T cells, but not on other cell types.33 Thus, blocking IL-7R functions has shown to be effective in suppressing adoptive transfer-induced intestinal inflammation in mice.34 "
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    ABSTRACT: The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn's disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed.
    Drug Design, Development and Therapy 11/2013; 7:1341-1357. DOI:10.2147/DDDT.S40107 · 3.03 Impact Factor
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    • "Excessive IL-7 activity has been shown to enhance effector T cell responses, preferentially Th1 and T cytotoxic (Tc) 1 responses, which are characterized by IFN-γ production [18-21]. Elevated IL-7 levels are associated with multiple autoimmune disorders [20,22] and in vivo loss-of-function studies demonstrate critical pathogenic roles of IL-7 in a variety of autoimmune diseases, including inflammatory bowel disease [23-25], rheumatoid arthritis [20,21], type-1 diabetes [17,26] and experimental autoimmune encephalomyelitis [18]. Similarly, pSS patients also have elevated IL-7 levels in the target organs and circulation [27]. "
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    ABSTRACT: Elevated IL-7 in the target tissues is closely associated with multiple autoimmune disorders, including Sjögren's syndrome (SS). We recently found that IL-7 plays an essential role in the development and onset of primary SS (pSS) in C57BL/6.NOD-Aec1Aec2 mice, a well-defined mouse model of primary SS. However, environmental signals that cause excessive IL-7 production are not well-characterized. Innate immune signaling plays a critical role in shaping the adaptive immune responses including autoimmune responses. We and others have previously shown that innate immune signaling can induce IL-7 expression in lungs and intestines of C57BL/6 mice. In this study, we characterized the effects of poly I:C, a double-stranded RNA analog and toll-like receptor 3 agonist, on the induction of IL-7 expression in salivary glands and on pSS development. We showed that poly I:C administration to C57BL/6 mice rapidly induced IL-7 expression in the salivary glands in a type 1 IFN- and IFN-γ-dependent manner. Moreover, poly I:C-induced IL-7 contributed to the optimal up-regulation of CXCL9 in the salivary glands, which may subsequently promote recruitment of more IFN-γ-producing T cells. Repeated administration of poly I:C to C57BL/6.NOD-Aec1Aec2 mice accelerated the development of SS-like exocrinopathy, and this effect was abolished by the blockade of IL-7 receptor signaling with a neutralizing antibody. Finally, poly I:C or a combination of IFN-α and IFN-γ induced IL-7 gene expression and protein production in a human salivary gland epithelial cell line. Hence, we demonstrate that IL-7 expression in the salivary gland cells can be induced by poly I:C and delineate a crucial mechanism by which innate immune signals facilitate the development of pSS, which is through induction of IL-7 in the target tissues.
    PLoS ONE 10/2013; 8(10):e77605. DOI:10.1371/journal.pone.0077605 · 3.23 Impact Factor
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    • "However, the adoptive transfer model of colitis is dependent on IL-7R-mediated expansion of T cells for induction of colitis, in contrast to our models wherein bacterial antigens drive inflammation and colitis involving resident host T cells (when present) and other innate immune cells. It is possible that IL-7R expression by cells other than CD4+ T cells has a modest effect in their model as they noted a trend of increased colitis scores in IL7R−/− x Rag2−/− recipients of wildtype naïve T cells compared to Rag2−/− -only recipients, although these differences were not significant [20]. "
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    ABSTRACT: Background Interleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer. Methods We examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb)-induced colitis in immune-sufficient Mdr1a−/− mice and in T- and B-cell-deficient Rag2−/− mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression. Results Treatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a−/− mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a−/− mice treated with an anti-IL-7R antibody. In Rag2−/− mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity. Conclusions Results from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in Hb-infected mice by controlling the expansion of multiple leukocyte populations, as well as the activity of these immune cells. Our findings demonstrate an important function of IL-7R-driven immunity in experimental colitis and indicate that the therapeutic efficacy of IL-7R blockade involves affecting both adaptive and innate immunity.
    Journal of Inflammation 10/2012; 9(1):39. DOI:10.1186/1476-9255-9-39 · 2.02 Impact Factor
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