Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk

Abstract

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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Figure 1: Deficiency in MHC class II protects mice from challenge with TLR ligands.
Figure 2: Deficiency in MHC class II protects mice from sepsis induced by live E. coli.
Figure 3: Deficiency in MHC class II attenuates TLR-triggered production of proinflammatory cytokines and type I interferon in macrophages and DCs.
Figure 4: Deficiency in MHC class II impairs the MyD88-dependent and TRIF-dependent activation of mitogen-activated protein kinases, NF-κB, IRF3 and IRF7 in TLR-triggered macrophages.
Figure 5: MHC class II molecules promote TLR-triggered inflammatory innate responses by maintaining Btk activation.
Figure 6: Intracellular MHC class II molecules interact with CD40 and Btk.
Figure 7: Activated Btk interacts with MyD88 and TRIF, promoting the activation of MyD88-dependent and TRIF-dependent pathways.

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Acknowledgements

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).

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X.C. and X.L. designed the experiments; X.L., Z.Z., D.L., L.X., F.M., P.Z. and H.Y. did the experiments; X.C. and X.L. analyzed data and wrote the paper; and X.C. was responsible for research supervision, coordination and strategy.

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Correspondence to Xuetao Cao.

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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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