Chronic antigen stimulation in vivo induces a distinct population of antigen-specific Foxp3-CD25- regulatory T cells

The concept of immune regulation/suppression has been well-established and, besides thymus-derived CD4(+)CD25(+) regulatory T (T-R) cells, it became clear that a variety of additional peripherally induced T-R cells play vital roles in protection from many harmful immune responses including intestinal inflammation. In the present study, we have analyzed in vivo-induced Ag-specific CD4(+) T-R cells with respect to their molecular and functional phenotype. By comparative genomics we could show that these Ag-specific T-R cells induced by chronic Ag stimulation in vivo clearly differ in their genetic program from naturally occurring thymus-derived CD4(+)CD25(+) T-R cells. This distinct population of induced T-R cells express neither CD25 nor the T-R-associated transcription factor Foxp3. Strikingly, CD25 is not even up-regulated upon stimulation. Despite the lack in Foxp3 expression, these in vivo-induced CD25(-) T-R cells are able to interfere with an Ag-specific CD8(+) T cell-mediated intestinal inflammation without significant increase in CD25 and Foxp3 expression. Thus, our results demonstrate that in vivo-induced Ag-specific T-R cells represent a distinct population of Foxp3(-)CD25(-) T-R cells with regulatory capacity both in vitro and in vivo.