Abstract
The molecular mechanisms that fine-tune Toll-like receptor (TLR)-triggered innate inflammatory responses remain to be fully elucidated. Major histocompatibility complex (MHC) molecules can mediate reverse signaling and have nonclassical functions. Here we found that constitutively expressed membrane MHC class I molecules attenuated TLR-triggered innate inflammatory responses via reverse signaling, which protected mice from sepsis. The intracellular domain of MHC class I molecules was phosphorylated by the kinase Src after TLR activation, then the tyrosine kinase Fps was recruited via its Src homology 2 domain to phosphorylated MHC class I molecules. This led to enhanced Fps activity and recruitment of the phosphatase SHP-2, which interfered with TLR signaling mediated by the signaling molecule TRAF6. Thus, constitutive MHC class I molecules engage in crosstalk with TLR signaling via the Fps–SHP-2 pathway and control TLR-triggered innate inflammatory responses.
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Change history
04 May 2012
In the version of this article initially published online, some labels in Figs. 3b and 7c were incorrect and the legend for Fig. 7c incorrectly identified the siRNA used. In Fig. 3b, the label 'siRNA:' (to identify the siRNA used) should be in the left margin adjacent to 'Ctrl'; the label 'MHCI' (to identify the protein detected) should be in the left margin below that. For Fig. 7c, the label above the right lane should read 'Fps'; its accompanying legend should end "...control or Fps-specific siRNA." The error has been corrected for the print, PDF and HTML versions of this article.
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Acknowledgements
We thank G. Feng (University of California, San Diego) for mice with loxP-flanked alleles encoding SHP-2; H. Shen (University of Pennsylvania School of Medicine) for L. monocytogenes; N. van Rooijen (Free University of Amsterdam) for liposomes; J. Long, X. Zuo and P. Ma for technical assistance; and T. Chen and Y. Han for discussions. Supported by the National Key Basic Research Program of China (2012CB910202 and 2010CB911903), the National 125 Key Project (2012ZX10002-014 and 2012AA020901), the National Natural Science Foundation of China (81123006) and the Shanghai Committee of Science and Technology (10DZ1910300).
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X.C. and S.X. designed the experiments; S.X., X.L., Y.B., C.H., X.Zhu, P.Z., W.L. and X.Zha. did the experiments; X.C., S.X. and X.L. analyzed data and wrote the paper; and X.C. was responsible for research supervision, coordination and strategy.
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Xu, S., Liu, X., Bao, Y. et al. Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps–SHP-2 pathway. Nat Immunol 13, 551–559 (2012). https://doi.org/10.1038/ni.2283
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DOI: https://doi.org/10.1038/ni.2283
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