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

Curtis Cai; Jerome Samir; Mehdi R. Pirozyan; Thiruni N. Adikari; Money Gupta; Preston Leung; Brendan Hughes; Willem Van der 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; Fabio Luciani

doi:10.1038/s41467-022-35281-7

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

Journal article

Open access

Peer reviewed

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

Curtis Cai, Jerome Samir, Mehdi R. Pirozyan, Thiruni N. Adikari, Money Gupta, Preston Leung, Brendan Hughes, Willem Van der Byl, Simone Rizzetto, Auda Elthala, …

Nature communications, Vol.13(1), 7543

2022

DOI: https://doi.org/10.1038/s41467-022-35281-7

PMCID: PMC9729230

PMID: 36477661

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Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

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.

Details

Title: Identification of human progenitors of exhausted CD8+T cells associated with elevated IFN-gamma response in early phase of viral infection
Authors/Creators: Curtis Cai - UNSW Sydney
Jerome Samir - UNSW Sydney
Mehdi R. Pirozyan - UNSW Sydney
Thiruni N. Adikari - UNSW Sydney
Money Gupta - UNSW Sydney
Preston Leung - UNSW Sydney
Brendan Hughes - UNSW Sydney
Willem Van der Byl - UNSW Sydney
Simone Rizzetto - UNSW Sydney
Auda Elthala - UNSW Sydney
Elizabeth Keoshkerian - UNSW Sydney
Jean-Louis Palgen - UNSW Sydney
Timothy Peters - Garvan Institute of Medical Research
Thi H. O. Nguyen - Peter Doherty Institute
Raymond Louie - Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia
Katherine Kedzierska - Peter Doherty Institute
Silvana Gaudieri - Murdoch University
Rowena A. Bull - UNSW Sydney
Andrew R. Lloyd - UNSW Sydney
Fabio Luciani - UNSW Sydney
Publication Details: Nature communications, Vol.13(1), 7543
Publisher: Springer Nature
Number of pages: 16
Grant note: 1128416; 1041897; 1084706 / NHMRC Research Fellowships; National Health and Medical Research Council (NHMRC) of Australia APP1148284; 1173871 / NHMRC; National Health and Medical Research Council (NHMRC) of Australia 1194036 / NHMRC Emerging Leadership Level 1 Investigator Grant; National Health and Medical Research Council (NHMRC) of Australia UNSW Hepatitis C Vaccine Initiative Australian Government Research Training Programme (RTP) Scholarship APP1121643; 1027551; 1060199; 1016351; 510488; 1053206; 630483 / National Health and Medical Research Council of Australia (NHMRC); National Health and Medical Research Council (NHMRC) of Australia
Identifiers: 991005623560607891
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.125 Hepatitis; 1.125.83 HCV
Web Of Science research areas: Immunology
ESI research areas: Immunology