A Comparative Study between T Regulatory Type 1 and CD4+CD25+ T Cells in the Control of Inflammation

There is now compelling evidence that CD4(+)CD25(+) T cells play a major role in the maintenance of tolerance. Besides CD4(+)CD25(+) T cells, different populations of regulatory CD4(+) T cells secreting high amounts of IL-10 (T regulatory type 1 (Tr1)) or TGF-beta (Th3) have also been described in in vivo models. In the lymphocyte transfer model of inflammatory bowel disease, we show here that the control of inflammation during the first weeks is not due to a complete inhibition of differentiation of aggressive proinflammatory T cells, but is the result of a balance between proinflammatory and Tr cells. We also show that in the first weeks continuous IL-10 secretion was required to actively control inflammation. Indeed, treatment with anti-IL-10R Abs 3 wk after the start of the experiment completely reversed the protective effect of Tr cells. IL-10 secretion and control of inflammation could be provided by late injection of Tr1 cells that efficiently cure ongoing inflammatory responses in two different models of inflammation. In contrast, inflammation was not controlled when high numbers of CD4(+)CD45RB(low) or CD4(+)CD25(+) T cells were injected as early as 1 wk after the start of the experiment. These results confirm in vitro studies showing that CD4(+)CD45RB(low) do not contain high IL-10-producing cells and suggest that CD4(+)CD45RB(low) Tr cells maintain tolerance in vivo, in part indirectly, through the differentiation of IL-10-secreting Tr1 cells.