title: Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients.
abstract: Chronic infection perturbs immune homeostasis. While prior studies have reported dysregulation of effector and memory cells, little is known about the effects on naïve T cell populations. We performed a cross-sectional study of chronic hepatitis C (cHCV) patients using tetramer-associated magnetic enrichment to study antigen-specific inexperienced CD8(+) T cells (i.e., tumor or unrelated virus-specific populations in tumor-free and sero-negative individuals). cHCV showed normal precursor frequencies, but increased proportions of memory-phenotype inexperienced cells, as compared to healthy donors or cured HCV patients. These observations could be explained by low surface expression of CD5, a negative regulator of TCR signaling. Accordingly, we demonstrated TCR hyperactivation and generation of potent CD8(+) T cell responses from the altered T cell repertoire of cHCV patients. In sum, we provide the first evidence that naïve CD8(+) T cells are dysregulated during cHCV infection, and establish a new mechanism of immune perturbation secondary to chronic infection.
authors.affiliation: Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France.|Centre d'Immunologie Humaine, Institut Pasteur, Paris, France.|Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Alanio
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, DNU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|Emory, , United States.
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicoli
authors.affiliation: Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France.|Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sultanik
authors.affiliation: The University Medical Center Freiburg, Department of Internal Medicine II, Albert-Ludwigs-Universität, Freiberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Flecken
authors.affiliation: Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France.|Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
authors.forename: Brieuc
authors.initials: B
authors.lastname: Perot
authors.affiliation: Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France.|Centre d'Immunologie Humaine, Institut Pasteur, Paris, France.|Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
authors.forename: Darragh
authors.initials: D
authors.lastname: Duffy
authors.affiliation: Immunoregulation Unit, Institut Pasteur, Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Plateforme d'Immunoscope, Institut Pasteur, Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.affiliation: Hôpital Saint-Louis, Assistance publique - hôpitaux de Paris, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Clave
authors.affiliation: Department of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marit M
authors.initials: MM
authors.lastname: van Buuren
authors.affiliation: Laboratoire de virologie, Hôpital Armand-Trousseau, Assistance publique - hôpitaux de Paris, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Schnuriger
authors.affiliation: Mathematics, Faculty of Engineering, Lunds University, Lund, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Johnsson
authors.affiliation: Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France.|Centre d'Immunologie Humaine, Institut Pasteur, Paris, France.|Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Boussier
authors.affiliation: Laboratoire de virologie, Hôpital Armand-Trousseau, Assistance publique - hôpitaux de Paris, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Garbarg-Chenon
authors.affiliation: APHP, Université Paris Descartes, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bousquet
authors.affiliation: Centre d'Immunologie Humaine, Institut Pasteur, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Mottez
authors.affiliation: Department of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: Hôpital Saint-Louis, Assistance publique - hôpitaux de Paris, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Toubert
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, DNU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|Emory, , United States.
authors.forename: Victor
authors.initials: V
authors.lastname: Appay
authors.affiliation: EFS, Hôpital Cochin, Paris, France.
authors.forename: Farhad
authors.initials: F
authors.lastname: Heshmati
authors.affiliation: The University Medical Center Freiburg, Department of Internal Medicine II, Albert-Ludwigs-Universität, Freiberg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.affiliation: APHP, Université Paris Descartes, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: APHP, Université Paris Descartes, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mallet
authors.affiliation: Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France.|Centre d'Immunologie Humaine, Institut Pasteur, Paris, France.|Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
mesh_terms: D018956:CD5 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003430:Cross-Sectional Studies; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000473:pathology*; D006801:Humans; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018956:CD5 Antigens; D011948:Receptors, Antigen, T-Cell
keywords: CD8 T cell dysfunction; Pre-immune repertoire; TCR signaling; chronic inflammation; human; human biology; immunology; medicine; viral immunology