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Glycolipid iGb3 feedback amplifies innate immune responses via CD1d reverse signaling

Cell Researchvolume 29pages4253 (2019) | Download Citation


The cross-talk between cellular lipid metabolism and the innate immune responses remains obscure. In addition to presenting lipid antigens to Natural Killer T-cells (NKT cells), the Cluster of Differentiation 1D Glycoprotein (CD1d) might mediate reverse signaling in antigen-presenting cells (APCs). Here we found CD1d deficiency attenuated Toll-like receptor (TLR)-triggered inflammatory innate responses in macrophages and dendritic cells, protecting mice from endotoxin shock. TLR activation in macrophages induced metabolic changes of glycosphingolipids (GSLs), among which glycolipid isoglobotrihexosylceramide (iGb3) was rapidly produced. The endogenously generated iGb3 bound CD1d in endosomal compartments and then synergized with the initially activated TLR signal to induce Tyr332 phosphorylation of CD1d intracellular domain. This led to the recruitment and activation of proline-rich tyrosine kinase 2 (Pyk2). Pyk2 interacted with IκB kinase β (IKKβ) and TANK-binding kinase 1 (TBK1), and enhanced tyrosine phosphorylation of Tyr188/199 of IKKβ and Tyr179 of TBK1 and thus, their activation to promote full activation of TLR signaling. Thus, intracellular CD1d reverse signaling, triggered by endogenous iGb3, amplifies inflammatory innate responses in APCs. Our findings identify a non-canonical function of CD1d reverse signaling activated by lipid metabolite in the innate immune response.

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We thank Dr. H. Shen (University of Pennsylvania) for Listeria monocytogenes; and X. Sun and M. Jin for technical assistance. This work was supported by the National Key Basic Research Program of China (2015CB964403 to X.C.), the National Natural Science Foundation of China (81788101 to X.C., 31570871 to X.L., 31770970 to X.L., 81600182 to P.Z., 81571543 to Y.L.), CAMS Innovation Fund for Medical Sciences (2016-12M-1-003 to X.C.), and “Shuguang Program” of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (18SG33 to X.L.).

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Author notes

  1. These authors contributed equally: Xingguang Liu, Peng Zhang, Yunkai Zhang


  1. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China

    • Xingguang Liu
    • , Peng Zhang
    • , Yunkai Zhang
    • , Sheng Xu
    • , Yingke Li
    • , Qingqing Zhou
    • , Xiang Chen
    • , Nan Li
    •  & Xuetao Cao
  2. Department of Haematology, General Hospital of Southern Theater Command, Guangzhou, 510000, China

    • Peng Zhang
  3. Laboratory of Cellular and Molecular Tumor Immunology, Institutes of Biology and Medical Sciences, Jiangsu Laboratory of Infection Immunity, Soochow University, Suzhou, 215123, China

    • Zheng Wang
    •  & Yunsen Li
  4. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China

    • Wanwan Huai
    • , Xi Chen
    •  & Xuetao Cao
  5. College of Pharmacy, Nankai University, Tianjin, 30071, China

    • Peng Wang
  6. College of Life Science, Nankai University, Tianjin, 30071, China

    • Xuetao Cao
  7. Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China

    • Xuetao Cao


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X.C. and X.L. conceived this project and supervised the experiments. X.C., X.L., P.Z. and Y.Z. wrote the paper. X.L., P.Z., Y.Z., Z.W., S.X., Y.L., W.H., Q.Z., X.C., X.C., N.L. P.W. and Y.L. performed the experiments and analyzed the data.

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The authors declare no competing interests.

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Correspondence to Xingguang Liu or Xuetao Cao.

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