National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
Nat Immunol. 2011 May;12(5):416-24. doi: 10.1038/ni.2015. Epub 2011 Mar 27.
The molecular mechanisms involved in the full activation of innate immunity achieved through Toll-like receptors (TLRs) remain to be fully elucidated. In addition to their classical antigen-presenting function, major histocompatibility complex (MHC) class II molecules might mediate reverse signaling. Here we report that deficiency in MHC class II attenuated the TLR-triggered production of proinflammatory cytokines and type I interferon in macrophages and dendritic cells, which protected mice from endotoxin shock. Intracellular MHC class II molecules interacted with the tyrosine kinase Btk via the costimulatory molecule CD40 and maintained Btk activation, but cell surface MHC class II molecules did not. Then, Btk interacted with the adaptor molecules MyD88 and TRIF and thereby promoted TLR signaling. Therefore, intracellular MHC class II molecules can act as adaptors, promoting full activation of TLR-triggered innate immune responses.
涉及 Toll 样受体 (TLRs) 实现固有免疫完全激活的分子机制仍有待充分阐明。除了它们经典的抗原呈递功能外，主要组织相容性复合体 (MHC) Ⅱ类分子可能介导反向信号。在这里，我们报告 MHC Ⅱ类分子缺陷会减弱巨噬细胞和树突状细胞中 TLR 触发的促炎细胞因子和 I 型干扰素的产生，从而保护小鼠免受内毒素休克。细胞内 MHC Ⅱ类分子通过共刺激分子 CD40 与酪氨酸激酶 Btk 相互作用并维持 Btk 激活，但细胞表面 MHC Ⅱ类分子则不会。然后，Btk 与衔接子分子 MyD88 和 TRIF 相互作用，从而促进 TLR 信号转导。因此，细胞内 MHC Ⅱ类分子可以作为衔接子，促进 TLR 触发的固有免疫反应的完全激活。
