Recent studies have described the ability of specific subsets of peripheral CD4+ T-cells to suppress chronic gut inflammation in immune-based models of inflammatory bowel disease (IBD). We have found that transfer of CD4+CD45RB[high] T-cells into athymic nu/nu (nude) mice fails to induce colitis whereas reconstitution with this same T-cell population into severe combined immunodeficient (SCID) or recombinase activating gene deficient (RAG -/-) mice induces severe colitis. These data suggest that in the absence of peripheral CD4+-T cells other lymphocyte populations may suppress the development of chronic colitis in this model. We provide preliminary data to suggest that intraepithelial lymphocytes (IELs) represent an equally important population of regulatory cells that act to prevent or limit the potentially injurious immune responses to enteric antigens. The overall objective of the present study is to better understand the mechanisms by which IELs prevent or limit chronic gut inflammation in vivo. Hypothesis: We propose that IELs represent an important regulatory cell population that are capable of inhibiting the initiation and progression of experimental colitis independent of peripheral CD4+ regulatory T-cells. This regulation may occur either through direct suppression of effector cell function or by promoting the polarization of naive CD4+ cells toward a non-pathogenic and/or regulatory phenotype. In addition, we propose that this suppressive activity of IELs is mediated by interleukin-10 (IL-10) and/or transforming growth factor-beta1 (TGF-beta). In order to test this hypothesis, we intend to: a) Determine whether IELs alone are capable of suppressing chronic colitis induced by the transfer of CD4+CD45RB[high] T-cells into immuno-deficient recipients. We will use two different approaches (i.e. radiation chimeras and breeding schemes) to generate immuno-deficient mice containing IELs but no T- or B-cells as well as mice containing B-cells but no IELs or T-cells; b) Define whether IELs regulate chronic gut inflammation by direct suppression of effector cell function or by promoting the polarization of naive CD4+CD45RB[high] T-cells toward a non-pathogenic and/or regulatory phenotype; and c) Identify whether IL-10 and/or TGF-beta mediate(s) the IEL-dependent suppression of chronic colitis in the CD45RB[high] T-cell/nude transfer model. Understanding the mechanisms by which IELs prevent or limit chronic gut inflammation may provide new insight into the pathophysiology of IBD.
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