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The lectin Siglec-G inhibits dendritic cell cross-presentation by impairing MHC class I–peptide complex formation

Nature Immunology volume 17, pages 11671175 (2016) | Download Citation

Abstract

CD8α+ dendritic cells (DCs) are specialized at cross-presenting extracellular antigens on major histocompatibility complex (MHC) class I molecules to initiate cytotoxic T lymphocyte (CTL) responses; however, details of the mechanisms that regulate cross-presentation remain unknown. We found lower expression of the lectin family member Siglec-G in CD8α+ DCs, and Siglec-G deficient (Siglecg−/−) mice generated more antigen-specific CTLs to inhibit intracellular bacterial infection and tumor growth. MHC class I–peptide complexes were more abundant on Siglecg−/− CD8α+ DCs than on Siglecg+/+ CD8α+ DCs. Mechanistically, phagosome-expressed Siglec-G recruited the phosphatase SHP-1, which dephosphorylated the NADPH oxidase component p47phox and inhibited the activation of NOX2 on phagosomes. This resulted in excessive hydrolysis of exogenous antigens, which led to diminished formation of MHC class I–peptide complexes for cross-presentation. Therefore, Siglec-G inhibited DC cross-presentation by impairing such complex formation, and our results add insight into the regulation of cross-presentation in adaptive immunity.

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Acknowledgements

We thank Y. Liu (Children's National Medical Center, Washington) for Siglecg−/− mice; H. Shen (University of Pennsylvania) for LM; H.Nie (Shanghai JiaoTong University) for the B16-OVA cell line; G. Liu (Chinese Academy of Sciences) for the plasmid pKSV7; S. Xu, Z. Jiang for technical assistance; and T. Chen and L. Lu for discussions. Supported by the National Key Basic Research Program of China (2013CB530502 and 2014CB542101), the National Natural Science Foundation of China (81522019, 31390431, 31270966 and 81471567) and the Shanghai Pujiang Program (14PJ1410800).

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Author notes

    • Yuanyuan Ding
    • , Zhenhong Guo
    •  & Yiqi Liu

    These authors contributed equally to this work.

Affiliations

  1. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.

    • Yuanyuan Ding
    • , Yiqi Liu
    •  & Xuetao Cao
  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.

    • Yuanyuan Ding
    • , Zhenhong Guo
    • , Qian Zhang
    • , Xiongfei Xu
    • , Yan Gu
    • , Yi Zhang
    •  & Xuetao Cao
  3. National Key Laboratory of Medical Molecular Biology & Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

    • Yuanyuan Ding
    • , Xia Li
    • , Dezhi Zhao
    •  & Xuetao Cao

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Contributions

Y.D., Z.G., Y.L., X.L. Q.Z., X.X., Y.G., Y.Z., and D.Z. performed the experiments; Y.D., Z.G. and X.C. analyzed data and wrote the manuscript; and X.C. designed and supervised the research.

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The authors declare no competing financial interests.

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Correspondence to Xuetao Cao.

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https://doi.org/10.1038/ni.3535

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