title: IL-12R beta 2 promotes the development of CD4+CD25+ regulatory T cells.
abstract: We have previously shown that mice lacking the IL-12-specific receptor subunit beta2 (IL-12Rbeta2) 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-12Rbeta2 impacts other autoimmune disorders similarly. In the present study we demonstrate that IL-12Rbeta2(-/-) mice develop earlier onset and more severe disease in the streptozotocin-induced model of diabetes, indicating predisposition of IL-12Rbeta2-deficient mice to autoimmune diseases. T cells from IL-12Rbeta2(-/-) 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-12Rbeta2(-/-) mice were comparable to those of WT mice. However, IL-12Rbeta2(-/-) 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-12Rbeta2(-/-) mice were less efficient than those from WT mice in suppressing effector T cells. The role of IL-12Rbeta2 in the induction of Tregs was confirmed using small interfering RNA. These findings suggest that signaling via IL-12Rbeta2 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.
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhao
authors.forename: Shuo
authors.initials: S
authors.lastname: Yu
authors.forename: Denise C
authors.initials: DC
authors.lastname: Fitzgerald
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elbehi
authors.forename: Bogoljub
authors.initials: B
authors.lastname: Ciric
authors.forename: A M
authors.initials: AM
authors.lastname: Rostami
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang