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.
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We thank P. Ma, M. Jin and Y. Li for technical assistance; and N. Li, H. An, T. Chen, S. Xu and C. Han for discussions. Supported by the National Key Basic Research Program of China (2007CB512403), National 115 Key Project (2008ZX10002-008, 2009ZX09503-023) and the National Natural Science Foundation of China (30721091).
The authors declare no competing financial interests.
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Liu, X., Zhan, Z., Li, D. et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat Immunol 12, 416–424 (2011). https://doi.org/10.1038/ni.2015
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