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Immunity. 2017 Oct 17;47(4):648-663.e8. doi: 10.1016/j.immuni.2017.09.006.

Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection.

Author information

1
Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg 67000, France; Université de Strasbourg, Strasbourg 67081, France.
2
Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
3
Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040, Brazil.
4
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg 67000, France; Université de Strasbourg, Strasbourg 67081, France.
5
Institute for Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf 40225, Germany.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
7
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
8
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
9
Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
10
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg 67000, France; Université de Strasbourg, Strasbourg 67081, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg 67000, France.
11
Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: glauer@mgh.harvard.edu.

Abstract

Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection.

KEYWORDS:

CD4 T cell help; CD8 T cells; T cell dysfunction; adaptive immunity; hepatitis C virus; metabolism; network analysis; nucleosome; transcriptional regulation; viral escape

PMID:
29045899
PMCID:
PMC5708133
DOI:
10.1016/j.immuni.2017.09.006
[Indexed for MEDLINE]
Free PMC Article

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