Zheng Song Guo, Wang Juhua, Horwitz David A
Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA 90033, USA.
J Immunol. 2008 Jun 1;180(11):7112-6. doi: 10.4049/jimmunol.180.11.7112.
TGF-beta has pleiotropic effects on T cell differentiation that are determined by other cytokines in the local environment. Whereas IL-2 and TGF-beta induce naive T cells to become forkhead/winged helix transcription factor (Foxp3) positive regulatory cells (iTregs), the combination of IL-6 and TGF-beta induces IL-17-producing cells (Th17). Moreover, IL-6 can use TGF-beta produced by thymus-derived natural regulatory T cells (nTregs) to convert them to Th17 cells. In this study, we report a major difference between iTregs and nTregs. Treatment of iTregs with IL-6 did not affect Foxp3 expression, and their suppressive activity in vitro and in vivo was intact. To explain this difference between nTregs and iTregs, we found that IL-2 and TGF-beta down-regulate IL-6 receptor expression and IL-6 signaling. The resistance of iTregs to Th17 conversion suggests that they can function more effectively than nTregs in an inflammatory milieu and emphasizes the central role of IL-2 in combination with TGF-beta to maintain immunologic homeostasis.
转化生长因子-β（TGF-β）对T细胞分化具有多效性作用，这些作用由局部环境中的其他细胞因子决定。白细胞介素-2（IL-2）和TGF-β可诱导初始T细胞成为叉头/翼状螺旋转录因子（Foxp3）阳性调节性细胞（诱导性调节性T细胞，iTregs），而IL-6和TGF-β的组合则诱导产生白细胞介素-17的细胞（辅助性T细胞17，Th17）。此外，IL-6可利用胸腺来源的天然调节性T细胞（nTregs）产生的TGF-β将其转化为Th17细胞。在本研究中，我们报告了iTregs和nTregs之间的一个主要差异。用IL-6处理iTregs并不影响Foxp3的表达，其在体外和体内的抑制活性均保持完整。为了解释nTregs和iTregs之间的这种差异，我们发现IL-2和TGF-β可下调IL-6受体表达和IL-6信号传导。iTregs对向Th17细胞转化的抗性表明，它们在炎症环境中比nTregs能更有效地发挥作用，并强调了IL-2与TGF-β联合在维持免疫稳态中的核心作用。
