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 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

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

Nat Commun. 2022 Dec 7;13(1):7543. doi: 10.1038/s41467-022-35281-7.

Authors

Curtis Cai^#^{1

2}, Jerome Samir^#^{1

2}, Mehdi R Pirozyan^{1

2}, Thiruni N Adikari^{1

2}, Money Gupta^{1

2}, Preston Leung^{1

2}, Brendan Hughes^{1

2}, Willem Van der Byl^{1

2}, Simone Rizzetto^{1

2}, Auda Elthala^{2

3}, Elizabeth Keoshkerian^{1

2}, Jean-Louis Palgen^{1

2}, Timothy Peters⁴, Thi H O Nguyen⁵, Raymond Louie^{1

2}, Katherine Kedzierska⁵, Silvana Gaudieri^{6

7

8}, Rowena A Bull^{1

2}, Andrew R Lloyd², Fabio Luciani^{9

10

11}

Affiliations

¹ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
² Kirby Institute for Infection and Immunity, University of New South Wales, Sydney, NSW, Australia.
³ Microsoft, Doha, Qatar.
⁴ Garvan Institute for Medical Research, Sydney, NSW, Australia.
⁵ Peter Doherty Institute, University of Melbourne, Melbourne, VIC, Australia.
⁶ School of Human Sciences, University of Western Australia, Perth, WA, Australia.
⁷ Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.
⁸ Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. [email protected].
¹⁰ Kirby Institute for Infection and Immunity, University of New South Wales, Sydney, NSW, Australia. [email protected].
¹¹ Garvan Institute for Medical Research, Sydney, NSW, Australia. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes*
Humans
Virus Diseases*