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Identification of human progenitors of exhausted CD8+ T cells associated with elevated IFN-γ response in early phase of viral infection

Author

Listed:
  • Curtis Cai

    (University of New South Wales
    University of New South Wales)

  • Jerome Samir

    (University of New South Wales
    University of New South Wales)

  • Mehdi R. Pirozyan

    (University of New South Wales
    University of New South Wales)

  • Thiruni N. Adikari

    (University of New South Wales
    University of New South Wales)

  • Money Gupta

    (University of New South Wales
    University of New South Wales)

  • Preston Leung

    (University of New South Wales
    University of New South Wales)

  • Brendan Hughes

    (University of New South Wales
    University of New South Wales)

  • Willem Byl

    (University of New South Wales
    University of New South Wales)

  • Simone Rizzetto

    (University of New South Wales
    University of New South Wales)

  • Auda Elthala

    (University of New South Wales
    Microsoft)

  • Elizabeth Keoshkerian

    (University of New South Wales
    University of New South Wales)

  • Jean-Louis Palgen

    (University of New South Wales
    University of New South Wales)

  • Timothy Peters

    (Garvan Institute for Medical Research)

  • Thi H. O. Nguyen

    (University of Melbourne)

  • Raymond Louie

    (University of New South Wales
    University of New South Wales)

  • Katherine Kedzierska

    (University of Melbourne)

  • Silvana Gaudieri

    (University of Western Australia
    Murdoch University
    Vanderbilt University Medical Center)

  • Rowena A. Bull

    (University of New South Wales
    University of New South Wales)

  • Andrew R. Lloyd

    (University of New South Wales)

  • Fabio Luciani

    (University of New South Wales
    University of New South Wales
    Garvan Institute for Medical Research)

Abstract

T cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of individuals with primary infection using single-cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-γ response against the transmitted virus is associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome, we find heterogeneous subsets of progenitors of exhaustion, based on the level of PD-1 expression and loss of AP-1 transcription factors. Intra-clonal analysis shows distinct trajectories with multiple fates and evolutionary plasticity of precursor cells. These findings challenge the current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T cell differentiation in human infections.

Suggested Citation

  • Curtis Cai & Jerome Samir & Mehdi R. Pirozyan & Thiruni N. Adikari & Money Gupta & Preston Leung & Brendan Hughes & Willem Byl & Simone Rizzetto & Auda Elthala & Elizabeth Keoshkerian & Jean-Louis Pal, 2022. "Identification of human progenitors of exhausted CD8+ T cells associated with elevated IFN-γ response in early phase of viral infection," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35281-7
    DOI: 10.1038/s41467-022-35281-7
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    Cited by:

    1. Raymond Hall Yip Louie & Curtis Cai & Jerome Samir & Mandeep Singh & Ira W. Deveson & James M. Ferguson & Timothy G. Amos & Helen Marie McGuire & Kavitha Gowrishankar & Thiruni Adikari & Robert Balder, 2023. "CAR+ and CAR− T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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