Gelman Andrew E, LaRosa David F, Zhang Jidong, Walsh Patrick T, Choi Yongwon, Sunyer J Oriol, Turka Laurence A
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19010, USA.
Immunity. 2006 Nov;25(5):783-93. doi: 10.1016/j.immuni.2006.08.023. Epub 2006 Oct 19.
While T cells respond directly to toll-like receptor (TLR) agonists, TLR-signaling pathways in T cells are poorly characterized. Here we demonstrate in CD4(+) T cells that CpG DNA directly enhances proliferation, prevents anergy, and augments humoral responses to a T cell-dependent antigen by a Myeloid differentiation primary-response protein 88 (MyD88) and Phosphatidylinositol 3-kinase (PI-3 kinase)-dependent pathway. PI-3 kinase activation required a putative Src-homology domain (SH2) binding motif in the MyD88 Toll-Like or IL-1 Receptor (TIR) domain. Reconstitution of MyD88-deficient primary T cells with a MyD88 transgene mutated in this motif abrogated association of PI-3 kinase with MyD88, phosphorylation of protein kinase B (Akt) and Glycogen Synthetase Kinase-3 (GSK-3), and interleukin-2 (IL-2) production. The MyD88 death domain, on the other hand, was required for NF-kB activation and survival. These studies identify a MyD88-dependent PI-3 kinase-signaling pathway in T cells that differentiates CpG DNA-mediated proliferation from survival and is required for an in vivo T cell-dependent immune response.
虽然T细胞可直接对Toll样受体（TLR）激动剂作出反应，但T细胞中的TLR信号通路却鲜为人知。在此，我们在CD4(+) T细胞中证明，CpG DNA通过髓样分化初级反应蛋白88（MyD88）和磷脂酰肌醇3激酶（PI-3激酶）依赖性途径，直接增强增殖、防止无反应性，并增强对T细胞依赖性抗原的体液反应。PI-3激酶的激活需要MyD88 Toll样或IL-1受体（TIR）结构域中的一个假定的Src同源结构域（SH2）结合基序。用在此基序中发生突变的MyD88转基因重建MyD88缺陷的原代T细胞，可消除PI-3激酶与MyD88的结合、蛋白激酶B（Akt）和糖原合成酶激酶-3（GSK-3）的磷酸化以及白细胞介素-2（IL-2）的产生。另一方面，MyD88死亡结构域是NF-κB激活和细胞存活所必需的。这些研究确定了T细胞中一条MyD88依赖性PI-3激酶信号通路，该通路可区分CpG DNA介导的增殖与存活，并且是体内T细胞依赖性免疫反应所必需的。
