IL-1β Promotes TGF-β1 and IL-2 Dependent Foxp3 Expression in Regulatory T Cells

Earlier, we have shown that GM-CSF-exposed CD8 alpha- DCs that express low levels of pro-inflammatory cytokines IL-12 and IL-1 beta can induce Foxp3+ Tregs leading to suppression of autoimmunity. Here, we examined the differential effects of IL-12 and IL-1 beta on Foxp3 expression in T cells when activated in the presence and absence of DCs. Exogenous IL-12 abolished, but IL-1 beta enhanced, the ability of GM-CSF-exposed tolerogenic DCs to promote Foxp3 expression. Pre-exposure of DCs to IL-1 beta and IL-12 had only a modest effect on Foxp3- expressing T cells; however, T cells activated in the absence of DCs but in the presence of IL-1 beta or IL-12 showed highly significant increase and decrease in Foxp3+ T cell frequencies respectively suggesting direct effects of these cytokines on T cells and a role for IL-1 beta in promoting Foxp3 expression. Importantly, purified CD4+ CD25+ cells showed a significantly higher ability to maintain Foxp3 expression when activated in the presence of IL-1 beta. Further analyses showed that the ability of IL-1 beta to maintain Foxp3 expression in CD25+ T cells was dependent on TGF beta 1 and IL-2 expression in Foxp3+ Tregs and CD25- effectors T cells respectively. Exposure of CD4+ CD25+ T cells to IL-1 beta enhanced their ability to suppress effector T cell response in vitro and ongoing experimental autoimmune thyroidits in vivo. These results show that IL-1 beta can help enhance/maintain Tregs, which may play an important role in maintaining peripheral tolerance during inflammation to prevent and/or suppress autoimmunity.