Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration

CD25(+)CD4(+) T cells are naturally occurring regulatory T cells that are a nergic and have suppressive properties. Although they can be isolated from the spleens of normal mice, there are limited studies on how they can be ac tivated or expanded in vivo. We found that oral administration of OVA to OV A TCR transgenic mice resulted in a modification of the ratio of CD25(+)CD4 (+) to CD25(-)CD4(+) cells with an increase of CD25(+)CD4+ T cells accompan ied by a decrease of CD25(-)CD4(+) T cells. The relative increase in CD25()CD4(+) T cells persisted for as long as 4 wk post feeding. We also found t hat CTLA-4 was dominantly expressed in CD25(+)CD4(+) T cells and there was an increase in the percentage of CD25(+)CD4(+) T cells expressing CTLA-4 in OVA-fed mice. In contrast to CD25-CD4+ cells, CD25(+)CD4(+) cells from fed mice proliferated only minimally to OVA or anti-CD3 and secreted IL-10 and elevated levels of TGF-beta, following anti-CD3 stimulation. CD25(+)CD4(+) cells from fed mice suppressed the proliferation of CD25-CD4+ T cells in v itro more potently than CD25(+)CD4(+) T cells isolated from unfed mice, and this suppression was partially reversible by IL-10 soluble receptor or TGF -beta soluble receptor and high concentration of anti-CTLA-4. With anti-CD3 stimulation, CD25(+)CD4(+) cells from unfed mice secreted IFN-gamma, where as CD25(+)CD4(+) cells from fed mice did not. Adoptive transfer of CD25(+)C D4(+) T cells from fed mice suppressed in vivo delayed-type hypersensitivit y responses in BALB/c mice. These results demonstrate an Ag-specific in viv o method to activate CD25(+)CD4(+) regulatory T cells and suggest that they may be involved in oral tolerance.