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

2008; American Association of Immunologists; Volume: 181; Issue: 6 Linguagem: Inglês

10.4049/jimmunol.181.6.3870

1550-6606

Zhao Zhao, Shuo Yu, Denise Fitzgerald, Mohamed El Behi, Bogoljub Ćirić, A. M. Rostami, Guang‐Xian Zhang,

Cytokine Signaling Pathways and Interactions

Abstract 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.