| The mucosal immune system manifests tolerance to commensal flora in the intestinal lumen, defined herein as natural tolerance. T cells in the lamina propria of the small and large bowel exhibit a characteristic hyporesponsive phenotype and are critical for maintaining this tolerant state. While cells resident to the lamina propria reinforce T cell hyporesponsiveness, demonstrated using mononuclear cells from the mouse small intestine, this distinct phenotype might also originate through T cell differentiation prior to migration into gut tissue. Peyer's patches, organized lymphoid aggregates within the wall of the small intestine, are the principal sites in which mucosal lymphocytes first encounter antigens derived from commensal flora. Furthermore, distinct sets of dendritic cells that populate Peyer's patches promote naïve T cells to secrete interleukin (IL)-10, an immunosuppressive cytokine. Therefore, I hypothesized that T cells exposed to antigen within the Peyer's patch microenvironment differentiate into specialized immunoregulatory T cell subsets central to promoting natural tolerance. These studies demonstrate that upon exposure to antigen within Peyer's patches, T cells acquire an activated and memory phenotype and exhibit characteristics consistent with that of regulatory T cells. In vitro, Peyer's patch mononuclear cells stimulated through their T cell receptor/CD3 complex suppress T cell proliferation partially mediated by IL-10 and transforming growth factor (TGF)-β secretion. Preliminary studies suggest that in vivo, Peyer's patch mononuclear cells ameliorate colitis in IL-10 deficient (IL-10−/−) animals. Taken together, the findings support the conclusion that T cells maintain natural tolerance in the intestinal mucosa through antigen education in Peyer's patches. |
