IL-12Rβ2 promotes the development of CD4+CD25+ regulatory T cells

We have previously shown that mice lacking the IL-12-specific receptor subunit beta 2 (IL-12R beta 2) develop more severe experimental autoimmune encephalomyelitis than wild-type (WT) mice. The mechanism underlying this phenomenon is not known; nor is it known whether deficiency of IL-12R beta 2 impacts other autoimmune disorders similarly. In the present study we demonstrate that IL-12R beta 2(-/-) mice develop earlier onset and more severe disease in the streptozotocin-induced model of diabetes, indicating predisposition of IL-12R beta 2-deficient mice to autoimmune diseases. T cells from IL-12R beta 2(-/-) mice exhibited significantly higher proliferative responses upon TCR stimulation. The numbers of naturally occurring CD25(+)CD4(+) regulatory T cells (Tregs) in the thymus and spleen of IL-12R beta 2(-/-) mice were comparable to those of WT mice. However, IL-12R beta 2(-/-) mice exhibited a significantly reduced capacity to develop Tregs upon stimulation with TGF-beta, as shown by significantly lower numbers of CD25(+)CD4(+) T cells that expressed Foxp3. Functionally, CD25(+)CD4(+) Tregs derived from IL-12R beta 2(-/-) mice were less efficient than those from WT mice in suppressing effector T cells. The role of IL-12R beta 2 in the induction of Tregs was confirmed using small interfering RNA. These findings suggest that signaling via IL-12R beta 2 regulates both the number and functional maturity of Treg cells, which indicates a novel mechanism underlying the regulation of autoimmune diseases by the IL-12 pathway.