However, selleck inhibitor DSS-resistance of Rag? mice was IL-7R-dependent as shown by the fact that Rag?IL-7R? mice lost around 20�C25% of their body weight and hardly recovered (Figure 6A). Figure 6 IL-7R signaling protects Rag? mice from DSS-induced colitis. DSS-induced colitis is more severe in WT than in Rag? mice, because IEC damage facilitates priming of commensal-specific, pro-inflammatory T cells [25], which aggravate disease. However, based on the aforementioned results we hypothesized that T cells may promote DSS-induced colitis in an antigen-independent fashion, namely via the blockade of IL-7R signaling in IEC. To test this, Rag?OT-I+ mice were treated with DSS. The kinetics of body weight loss was nearly identical to Rag?IL-7R? mice (Figure 6A).

Importantly, CD8+ T cells from DSS-treated Rag?OT-I+ mice did not show any signs of activation and had a na?ve phenotype (Figure S7). Hence, the presence of naive, IL-7-consuming CD8+ T cells is sufficient to block the protective effect of IL-7 in DSS-treated Rag? mice. As expected, tissue damage and leukocyte infiltration were most pronounced in WT mice (Figure 6B and C). In contrast, Rag? colon samples showed only mild alterations as compared to untreated controls. However, tissue damage and leukocyte infiltration were clearly more pronounced in Rag?IL-7R? and Rag?OT-I+ mice as compared to DSS-treated Rag? mice (Figure 6B and C). In summary, our results demonstrate that IL-7 protects Rag? mice from DSS-induced tissue damage and subsequent colitis. Discussion CD4+ T cells recognizing antigens derived from the commensal microflora cause colitis under lymphopenic conditions [26].

Since IL-7 is a potent activation, growth and survival factor for T cells, it promotes intestinal damage via its action on T cells [9], [11], [12], [27]. Here we provide evidence that IL-7 regulates IEC homeostasis in the colon and protects lymphopenic mice from DSS-induced colitis. We show that IL-7-producing IEC accumulate in the intestine of Rag? mice (Figure 1). This requires IL-7R signaling, correlates with increased rates of IEC proliferation and survival and results in IEC hyperplasia (Figure 2A�CC). IEC are the major source of IL-7 in the colon [20] and express IL-7R, which are functional in vitro (Figure 3) and in vivo (Figure S3). This suggests that IL-7R signaling in IEC contributes to the regulation of intestinal homeostasis.

Nevertheless, we cannot formally exclude indirect effects of IL-7, e.g. on innate lymphoid cells (ILC). IL-22-producing ILC are important regulators of intestinal homeostasis [28], they are generated in an IL-7/IL-7R-dependent fashion [29], [30] and protect Rag? mice from DSS-induced colitis [31], [32]. Therefore, the lack of ILC may promote alterations in IEC homeostasis and aggravate Batimastat DSS-induced colitis in Rag?IL-7R? mice (Figure 2 and and66). Nevertheless, the lack of ILC does not explain the results we have obtained with IL-7R-competent Rag? mice.