Identification of human progenitors of exhausted CD8 + T cells associated with elevated IFN-γ response in early phase of viral infection.
Curtis CaiJerome SamirMehdi R PirozyanThiruni N AdikariMoney GuptaPreston LeungBrendan HughesWillem Van Der BylSimone RizzettoAuda ElthalaElizabeth KeoshkerianJean-Louis PalgenTimothy J PetersThi H O NguyenRaymond H Y LouieKatherine KedzierskaSilvana GaudieriRowena A BullAndrew R LloydFabio LucianiPublished in: Nature communications (2022)
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.
Keyphrases
- hepatitis c virus
- early onset
- human immunodeficiency virus
- endothelial cells
- single cell
- transcription factor
- sars cov
- late onset
- induced apoptosis
- dendritic cells
- poor prognosis
- immune response
- healthcare
- pluripotent stem cells
- rna seq
- high throughput
- genome wide
- gene expression
- machine learning
- endoplasmic reticulum stress
- current status
- deep learning
- young adults
- cross sectional
- peripheral blood
- cell death
- dna methylation
- antiretroviral therapy