title: Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection.
abstract: T cell exhaustion is common during chronic infections. Although CD4(+) T cells are critical for controlling viral load during chronic viral infections, less is known about their differentiation and transcriptional program. We defined the phenotypic, functional, and molecular profiles of exhausted CD4(+) T cells. Global transcriptional analysis demonstrated a molecular profile distinct from effector and memory CD4(+) T cells and also from exhausted CD8(+) T cells, though some common features of CD4(+) and CD8(+) T cell exhaustion were revealed. We have demonstrated unappreciated roles for transcription factors (TFs) including Helios, type I interferon (IFN-I) signaling, and a diverse set of coinhibitory and costimulatory molecules during CD4(+) T cell exhaustion. Moreover, the signature of CD4(+) T cell exhaustion was found to be distinct from that of other CD4(+) T cell lineage subsets and was associated with TF heterogeneity. This study provides a framework for therapeutic interventions targeting exhausted CD4(+) T cells.
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Alison
authors: A
authors: Crawford
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Jill M
authors: JM
authors: Angelosanto
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Charlly
authors: C
authors: Kao
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Travis A
authors: TA
authors: Doering
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Pamela M
authors: PM
authors: Odorizzi
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Burton E
authors: BE
authors: Barnett
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: wherry@mail.med.upenn.edu.
authors: E John
authors: EJ
authors: Wherry
mesh_terms: D001424:Bacterial Infections / Q000276:immunology*; D058491:Bacterial Load; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002908:Chronic Disease; D003141:Communicable Diseases / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D019562:Viral Load; D014777:Virus Diseases / Q000276:immunology*