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

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 Palgen, Timothy Peters, Thi H. O. Nguyen, Raymond Louie, Katherine Kedzierska, Silvana Gaudieri, Rowena A. Bull, Andrew R. Lloyd and Fabio Luciani ()
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Curtis Cai: University of New South Wales
Jerome Samir: University of New South Wales
Mehdi R. Pirozyan: University of New South Wales
Thiruni N. Adikari: University of New South Wales
Money Gupta: University of New South Wales
Preston Leung: University of New South Wales
Brendan Hughes: University of New South Wales
Willem Byl: University of New South Wales
Simone Rizzetto: University of New South Wales
Auda Elthala: University of New South Wales
Elizabeth Keoshkerian: University of New South Wales
Jean-Louis Palgen: 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
Katherine Kedzierska: University of Melbourne
Silvana Gaudieri: University of Western Australia
Rowena A. Bull: University of New South Wales
Andrew R. Lloyd: University of New South Wales
Fabio Luciani: University of New South Wales

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35281-7

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