Abstract
NOD-like receptors (NLRs) are a family of intracellular proteins that play critical roles in innate immunity against microbial infection. NLRC5, the largest member of the NLR family, has recently attracted much attention. However, in vitro studies have reported inconsistent results about the roles of NLRC5 in host defense and in regulating immune signaling pathways. The in vivo function of NLRC5 remains unknown. Here, we report that NLRC5 is a critical regulator of host defense against intracellular pathogens in vivo. NLRC5 was specifically required for the expression of genes involved in MHC class I antigen presentation. NLRC5-deficient mice showed a profound defect in the expression of MHC class I genes and a concomitant failure to activate L. monocytogenes-specific CD8+ T cell responses, including activation, proliferation and cytotoxicity, and the mutant mice were more susceptible to the pathogen infection. NLRP3-mediated inflammasome activation was also partially impaired in NLRC5-deficient mice. However, NLRC5 was dispensable for pathogen-induced expression of NF-κB-dependent pro-inflammatory genes as well as type I interferon genes. Thus, NLRC5 critically regulates MHC class I antigen presentation to control intracellular pathogen infection.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (30930084, 91029708 and 30871298), the National Basic Research Program of China (973 program; 2010CB529705), the Chinese Academy of Sciences (KSCX2-YW-R-146) and the Science and Technology Commission of Shanghai Municipality (10JC1416600). It was also supported by the Shanghai Hospital Science & Technology Resource Sharing Program funded by Shanghai Shenkang Hospital Development Center (SHDC12007708).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
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Supplementary information, Figure S1
The targeting strategy and genotyping of Nlrc5−/− mice. (PDF 73 kb)
Supplementary information, Figure S2
NLRC5 regulates MHC class I gene expression. (PDF 138 kb)
Supplementary information, Figure S3
NLRC5 regulates CD8+ but not CD4+ T cell activation. (PDF 122 kb)
Supplementary information, Figure S4
TCR activation-induced signaling and IFNγ production is normal in Nlrc5-deficient CD8+ T cells. (PDF 81 kb)
Supplementary information, Figure S5
NLRC5 promotes NLRP3 inflammasome activation. (PDF 124 kb)
Supplementary information, Figure S6
NLRC5 does not affect LPS-, poly(I:C)- or poly(dA:dT)-induced expression of NF-κB-dependent genes. (PDF 140 kb)
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Yao, Y., Wang, Y., Chen, F. et al. NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens. Cell Res 22, 836–847 (2012). https://doi.org/10.1038/cr.2012.56
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DOI: https://doi.org/10.1038/cr.2012.56
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