Dominitzki Sabine, Fantini Massimo C, Neufert Clemens, Nikolaev Alexei, Galle Peter R, Scheller Jürgen, Monteleone Giovanni, Rose-John Stefan, Neurath Markus F, Becker Christoph
Laboratory of Immunology, Medical Clinic I, University of Mainz, Mainz, Germany.
J Immunol. 2007 Aug 15;179(4):2041-5. doi: 10.4049/jimmunol.179.4.2041.
Chronic inflammatory diseases may develop when regulatory T cells (Tregs) fail to control the balance between tolerance and immunity. Alternatively, activated immune cells might prevent the induction or activation of Tregs in such diseases. In this study, we demonstrate that trans-signaling into T cells via the soluble IL-6 receptor completely abrogates the de novo induction of adaptive Tregs. Mechanistically, IL-6 trans-signaling augmented the expression of the TGF-beta signaling inhibitor SMAD7. Consequently, SMAD7 overexpression in T cells using newly created transgenic mice rendered CD4(+)CD25(-) T cells resistant to the induction of FoxP3. Finally, IL-6 trans-signaling inhibited Treg-mediated suppression in a murine model of colitis. In summary, IL-6 trans-signaling into T cells emerges as a key pathway for blockade of the development of adaptive Tregs and thus may play a pivotal role in shifting the balance between effector and regulatory T cell numbers in chronic inflammatory and autoimmune diseases.
当调节性T细胞（Tregs）无法控制耐受与免疫之间的平衡时，可能会引发慢性炎症性疾病。另外，在这类疾病中，活化的免疫细胞可能会阻止Tregs的诱导或活化。在本研究中，我们证明通过可溶性IL-6受体向T细胞进行转信号传导会完全消除适应性Tregs的从头诱导。从机制上讲，IL-6转信号传导增强了TGF-β信号传导抑制剂SMAD7的表达。因此，使用新创建的转基因小鼠使T细胞中SMAD7过表达，导致CD4(+)CD25(-) T细胞对FoxP3的诱导产生抗性。最后，在小鼠结肠炎模型中，IL-6转信号传导抑制了Treg介导的抑制作用。总之，向T细胞进行IL-6转信号传导成为阻碍适应性Tregs发育的关键途径，因此可能在慢性炎症和自身免疫性疾病中调节效应T细胞和调节性T细胞数量之间的平衡方面发挥关键作用。
