Joss A, Akdis M, Faith A, Blaser K, Akdis C A
Swiss Institute of Allergy and Asthma Research, Davos.
Eur J Immunol. 2000 Jun;30(6):1683-90. doi: 10.1002/1521-4141(200006)30:6<1683::AID-IMMU1683>3.0.CO;2-A.
IL-10 induces T cell anergy in numerous mouse models and specific immunotherapy of allergy in humans. Here, we demonstrate that IL-10 directly acts on T cells which are stimulated via CD28 by efficiently blocking proliferation and cytokine production. T cells tolerized by IL-10 showed high viability and the unresponsive state was reversed by anti-CD3 monoclonal antibody (mAb) stimulation and IL-2, but not by anti-CD28 mAb stimulation. Signal transduction via CD28 requires CD28 tyrosine phosphorylation and binding of phosphatidylinositol 3-kinase. IL-10 inhibited tyrosine phosphorylation of CD28; thus, the phosphatidylinositol 3-kinase binding to CD28 was blocked. Consequently, IL-10 inhibited the antigen-induced secretion of both Th1 and Th2 cytokines, including IL-2, IFN-gamma, IL-4, IL-5 and IL-13. Furthermore, neutralization of endogenously produced IL-10 significantly increased T cell proliferation and both Th1 and Th2 cytokine production in vitro. Using superantigen stimuli, T cell suppression by IL-10 was merely induced at low doses when co-stimulation by CD28 was essential. Together, these data demonstrate that IL-10 directly acts on the CD28 signaling pathway and this represents an important T cell suppression mechanism leading to anergy.
白细胞介素-10（IL-10）在众多小鼠模型中可诱导T细胞无能，并可用于人类过敏的特异性免疫治疗。在此，我们证明IL-10可直接作用于通过CD28刺激的T细胞，有效阻断其增殖和细胞因子产生。被IL-10耐受的T细胞具有高活力，其无反应状态可通过抗CD3单克隆抗体（mAb）刺激和IL-2逆转，但不能通过抗CD28 mAb刺激逆转。通过CD28的信号转导需要CD28酪氨酸磷酸化以及磷脂酰肌醇3激酶的结合。IL-10抑制CD28的酪氨酸磷酸化；因此，与CD28结合的磷脂酰肌醇3激酶被阻断。结果，IL-10抑制了包括IL-2、干扰素-γ、IL-4、IL-5和IL-13在内的Th1和Th2细胞因子的抗原诱导分泌。此外，在体外，中和内源性产生的IL-10可显著增加T细胞增殖以及Th1和Th2细胞因子的产生。使用超抗原刺激时，仅在低剂量且CD28共刺激必不可少的情况下，IL-10才会诱导T细胞抑制。总之，这些数据表明IL-10直接作用于CD28信号通路，这代表了一种导致无能的重要T细胞抑制机制。
