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

• Published in: Immunity (Cambridge, Mass.) Vol. 47; no. 4; pp. 648 - 663.e8
• Main Authors: Wolski, David, Foote, Peter K., Chen, Diana Y., Lewis-Ximenez, Lia L., Fauvelle, Catherine, Aneja, Jasneet, Walker, Andreas, Tonnerre, Pierre, Torres-Cornejo, Almudena, Kvistad, Daniel, Imam, Sabrina, Waring, Michael T., Tully, Damien C., Allen, Todd M., Chung, Raymond T., Timm, Jörg, Haining, W. Nicholas, Kim, Arthur Y., Baumert, Thomas F., Lauer, Georg M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.10.2017; Elsevier Limited; Elsevier
• Subjects: Acute Disease; adaptive immunity; Adaptive Immunity - genetics; Adaptive Immunity - immunology; Adult; Aged; CD4 antigen; CD4 T cell help; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; CD8 antigen; CD8 T cells; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - virology; Cell differentiation; Chronic infection; Cluster Analysis; Critical care; Differentiation (biology); Divergence; Effector cells; Exhaustion; Female; Gene expression; Gene Expression Profiling - methods; Gene regulation; Gene Regulatory Networks - immunology; Genetic Variation - immunology; Hepacivirus - immunology; Hepacivirus - physiology; Hepatitis; Hepatitis C; hepatitis C virus; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Human health and pathology; Humans; Hépatology and Gastroenterology; Immunological memory; Immunology; Infections; Inflammation; Inflammatory response; Life Sciences; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Male; Memory cells; metabolism; Middle Aged; Multivariate Analysis; network analysis; nucleosome; Singers; Studies; T cell dysfunction; T cell receptors; Time Factors; Transcription; Transcription, Genetic - immunology; transcriptional regulation; viral escape; Viral infections; Viruses; Young Adult; CD4 T cell help; viral escape; transcriptional regulation; hepatitis C virus; nucleosome; metabolism; network analysis; CD8 T cells; T cell dysfunction; adaptive immunity; CD4 T cell help; CD8 T cells
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2017.09.006

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. [Display omitted] •Disease outcome and viral escape are linked to transcriptional differences in T cells•T cells from different outcomes share a core of co-regulated T cell identity genes•Metabolic, nucleosome, and immune genes are dysregulated early in chronic infection•Dysregulation correlates with sex, age, and presence of HCV-specific CD4 T cells Wolski et. al show that transcriptional dysregulation of metabolic, nucleosomal, and immune processes in virus-specific CD8+ T cells during early persistent HCV infection is both under tight transcriptional control and associated with differences in predictors of disease outcome, like patient sex, age, and the presence of HCV-specific CD4+ T cells.