Figure 4 IL-7 promotes IEC proliferation and survival. Due to the lack of IL-7-consuming T cells, IL-7 availability is increased in Rag? mice [5]. This suggested to us that the intestinal epithelium responds to elevated IL-7 levels. To selleck chemicals Sunitinib test this hypothesis, colon sections from IL-7 transgenic (tg) mice [22] were analyzed. As shown in Figure 4C, their colonic epithelium was hyperplastic and contained far more Ki67+ cells than that of non-transgenic WT mice (Figure 4D). Thus, IL-7 overabundance is sufficient to cause IEC hyperplasia. IL-7 can induce nuclear translocation of ��-catenin [23], a central regulator of IEC homeostasis [24]. In the nucleus, ��-catenin binds to transcription factors of the T cell factor/lymphocyte enhancer factor (TCF/LEF) family to activate genes promoting proliferation, survival, differentiation and positioning of IEC [24].

In the WT colon, nuclear ��-catenin is mainly restricted to the crypt base [24] (data not shown). Accordingly, luminal IEC of PBS-treated Rag?IL-7? mice were nearly devoid of nuclear ��-catenin (Figure 4E). In contrast, IL-7-treatment caused the accumulation of ��-catenin in the nucleus of luminal IEC (Figure 4E). Similar results were obtained with IL-7tg mice (Figure 4F). Hence, IL-7 overabundance is associated with the accumulation of nuclear ��-catenin in luminal IEC and IEC hyperplasia. T lymphocytes prevent IEC hyperplasia and promote colitis in an antigen-independent, IL-7R-dependent fashion Having shown that lymphopenia-associated IL-7 overabundance promotes IEC hyperplasia, we asked next whether IL-7 consumption by T cells is sufficient to normalize IEC homeostasis in Rag? mice.

For this purpose, Rag? mice were reconstituted with polyclonal CD4+ and CD8+ T lymphocytes and colon sections were analyzed 85 days later. As compared to untreated Rag? controls, colon wall thickness (Figure 5A) and the number of Ki67+ cells (Figure 5B and D) were reduced in T cell-reconstituted Rag? mice. Simultaneously, the number of apoptotic cleaved caspase 3+ and Gob5+ cells (Figure 5D) was elevated after T cell reconstitution. Additionally, nuclear ��-catenin was hardly detectable in luminal IEC of T cell-reconstituted Rag? mice (Figure 5D). In agreement with reduced IEC numbers and a normalization of IEC homeostasis, BL was strongly reduced in the intestine of T cell-reconstituted Rag?IL-7GCDL mice (Figure S4).

In contrast, T cell reconstitution did not lead to any overt changes in the colonic epithelium of Rag?IL-7R? control mice (Figure 5A and B). Similarly, IEC homeostasis remained unaltered in Rag? mice reconstituted with IL-7R? T cells (Figure S5). However, at this stage Cilengitide we could not exclude that antigen-recognition and activation of the transferred T cells, in conjunction with IL-7R signaling, caused the subsequent regulation of IEC homeostasis. To test this possibility, the colon of Rag? OT-I+ TCR-transgenic (Rag?OT-I+) mice was analyzed.