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IL-12Rβ2 Promotes the Development of CD4+CD25+ Regulatory T Cells1

We have previously shown that mice lacking the IL-12-specific receptor subunit β2 (IL-12Rβ2) 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-12Rβ2 impacts other autoimmune disorders similarly. In the present study we demonstrate that IL-12Rβ2−/− mice develop earlier onset and more severe disease in the streptozotocin-induced model of diabetes, indicating predisposition of IL-12Rβ2-deficient mice to autoimmune diseases. T cells from IL-12Rβ2−/− 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-12Rβ2−/− mice were comparable to those of WT mice. However, IL-12Rβ2−/− mice exhibited a significantly reduced capacity to develop Tregs upon stimulation with TGF-β, as shown by significantly lower numbers of CD25+CD4+ T cells that expressed Foxp3. Functionally, CD25+CD4+ Tregs derived from IL-12Rβ2−/− mice were less efficient than those from WT mice in suppressing effector T cells. The role of IL-12Rβ2 in the induction of Tregs was confirmed using small interfering RNA. These findings suggest that signaling via IL-12Rβ2 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.