Summary Gαi2‐deficient mice, which spontaneously develop colitis, have previously been reported to have an increased frequency of mature, single positive thymocytes compared to wild‐type mice. In this study we further characterized the intrathymic changes in these mice before and during overt colitis. Even before the onset of colitis, Gαi2–/– thymi weighed less and contained fewer thymocytes, and this was exacerbated with colitis development. Whereas precolitic Gαi2–/– mice had unchanged thymocyte density compared to Gαi2+/– mice of the same age, this was significantly decreased in mice with colitis. Thymic atrophy in Gαi2–/– mice involved mainly the cortex. Using a five‐stage phenotypic characterization of thymocyte maturation based on expression of CD4, CD8, TCRαβ, CD69 and CD62L, we found that both precolitic and colitic Gαi2–/– mice had significantly increased frequencies of mature single‐positive CD4+ and CD8+ medullary thymocytes, and significantly reduced frequencies and total numbers of immature CD4+ CD8+ double‐positive thymocytes compared to Gαi2+/– mice. Furthermore, cortical and transitional precolitic Gαi2–/– thymocytes showed significantly reduced chemotactic migration towards CXCL12, and a trend towards reduced migration to CCL25, compared to wild‐type thymocytes, a feature even more pronounced in colitic mice. This impaired chemotactic migration of Gαi2–/– thymocytes could not be reversed by increased chemokine concentrations. Gαi2–/– thymocytes also showed reduced expression of the CCL25 receptor CCR9, but not CXCR4, the receptor, for CXCL12. Finally, wild‐type colonic lamina propria lymphocytes migrated in response to CXCL12, but not CCL25 and, as with thymocytes, the chemokine responsiveness was significantly reduced in Gαi2–/– mucosal lymphocytes.

Targeted deletion of the heterotrimeric G protein, Gai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on a4 integrins. In previous studies, short-term administration of anti-a4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-a4 integrin antibodies on colitis in Gai2 -/-mice. Long-term blockade of a4 integrin significantly increased the severity of colitis in Gai2 -/-mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1b, TNF-a and IFN-c. Blockade of a4 integrin reduced the recruitment of activated T cells to the small intestine. In strong contrast, there were significantly higher numbers of activated T cells in the colonic lamina propria and epithelium, most probably due to in situ proliferation. Furthermore, treatment with a4 integrin antibodies induced decreased levels of total IgA and IgG in sera, whereas total IgM levels were unchanged. These new findings may have implications in the understanding of the progression of chronic intestinal inflammation.See accompanying commentary: http://dx

We investigated dietary antigen-specific T-cell responses in mesenteric lymph nodes (MLN) and Peyer's patches (PP) in noncolitic control mice as well as in colitis-prone mice prior to onset of histological active colitis. T cells were restimulated in vitro with constituents isolated from the mouse diet. Interestingly, MLN

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The increased serum concentrations of IL-18 and IL-1Ra in established diseases are suggested as markers of ongoing colitis. Interestingly, the significantly increased serum concentration of IL-1Ra in pre-colitic mice is found to be an early marker of disease progression.