Article

Identification of Zika virus epitopes reveals immunodominant and protective roles for dengue virus cross-reactive CD8+ T cells

  • Nature Microbiology 2, Article number: 17036 (2017)
  • doi:10.1038/nmicrobiol.2017.36
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Abstract

CD8+ T cells play an important role in controlling Flavivirus infection, including Zika virus (ZIKV). Here, we have identified 25 HLA-B*0702-restricted epitopes and 1 HLA-A*0101-restricted epitope using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and intracellular cytokine staining (ICS) in ZIKV-infected IFN-α/β receptor-deficient HLA transgenic mice. The cross-reactivity of ZIKV epitopes to dengue virus (DENV) was tested using IFN-γ-ELISPOT and IFN-γ-ICS on CD8+ T cells from DENV-infected mice, and five cross-reactive HLA-B*0702-binding peptides were identified by both assays. ZIKV/DENV cross-reactive CD8+ T cells in DENV-immune mice expanded post ZIKV challenge and dominated in the subsequent CD8+ T cell response. ZIKV challenge following immunization of mice with ZIKV-specific and ZIKV/DENV cross-reactive epitopes elicited CD8+ T cell responses that reduced infectious ZIKV levels, and CD8+ T cell depletions confirmed that CD8+ T cells mediated this protection. These results identify ZIKV-specific and ZIKV/DENV cross-reactive epitopes and demonstrate both an altered immunodominance pattern in the DENV-immune setting relative to naive, as well as a protective role for epitope-specific CD8+ T cells against ZIKV. These results have important implications for ZIKV vaccine development and provide a mouse model for evaluating anti-ZIKV CD8+ T cell responses of human relevance.

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Acknowledgements

This research was funded by National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) grant no. 1R01 AI116813 (S.S.), NIH contracts (nos. HHSN272200900042C and HHSN27220140045C, to A.S.) and the La Jolla Institute for Allergy & Immunology institutional support (to S.S.).

Author information

Affiliations

  1. Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, California 92037, USA

    • Jinsheng Wen
    • , William Weihao Tang
    • , Nicholas Sheets
    • , Julia Ellison
    • , Kenneth Kim
    •  & Sujan Shresta
  2. Institute of Arboviruses, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China

    • Jinsheng Wen
  3. Division of Vaccine Discovery, La Jolla Institute for Allergy & Immunology, La Jolla, California 92037, USA

    • Alessandro Sette

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Contributions

J.W. and S.S. designed the project and experiments. A.S. provided the HLA transgenic mice. J.W., W.W.T. and N.S. performed the experiments. J.W., J.E., K.K. and S.S. interpreted the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sujan Shresta.

Supplementary information

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    Supplementary Information

    Supplementary Figures 1-5 and Supplementary Table 1.

Excel files

  1. 1.

    Supplementary Table 2

    Summary of group sizes of all experiments.

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    Supplementary Table 3

    Exact P values.