Molecular biology of extrathymic T cells for the development of mucosal inflammation

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IL-10 is an important regulatory cytokine in the mucosal immune system, as supported by the fact that mice deficient in IL-10 spontaneously develop Crohn's disease-like colitis. An aberrant, Th1-driven CD4^+ T-cell response to enteric bacteria seems to be important in the pathogenesis of this murine colitis. However, no specific bacteria or bacterial products have been identified, whether the colitis is mediated by the activation of CD4^+ T cells that recognize specific peptide-MHC complexes is controversial. In this study, we analyzed the TCRβ chain CDR3 length spectratype of colonic CD4^+ T cells isolated from diseased IL-10-deficient mice by using the Immunoscope technique. Screening of the diseased interleukin-10 deficient mice resulted in a restricted clonotype in TCR Vβ 13 and 14 subfamilies of colonic CD4^+ T cells. In contrast, a Gaussian distribution of clonotype of individual TCR Vβ subsets was observed in CD4^+ T cells from the peripheral lymphoid tissues. Although individua … More l variability in the disease-related response was also noted in other IL-10-deficient mice maintained in La Jolla and Osaka, perhaps because of different stages of the disease, genetic background, or the housing environment, colitis-related public clones seemed to be shared in all the tested diseased mice. To address whether public clones were involved, we determined DNA sequence of the clones. Public motifs were shared in colonic CD4^+ T cells from different background interleukin-10 deficient mice with colitis. The frequently found motifs were SXDWG and SATGNYAEQ. These motifs were not seen in the peripheral lymphoid tissues of diseased mice as well as the colon of nondiseased mice. Thus, the common motif may be related to a public gut-derived antigen, which could be important for the development of pathogenic CD4^+ T cells in this IBD model. The selection of Vβ-Jβ usage is perhaps stochastic in individual mice ; however, the epigenetic generation of SXDWG motif by the recombination machinery and selection for this motif in the gut environment could be : important for triggering IBD. Less