Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality during chronic hepatitis C virus infection.
Although chronic viral infections have evolved mechanisms to interfere with aspects of pathogen recognition by dendritic cells (DCs), the role that these APCs play in virus-specific T cell exhaustion is unclear. Herein we report that NS3-dependent suppression of Toll/IL-1 domain-containing adapter-inducing IFN-beta- and IFN-beta promoter stimulator-1- but not MyD88-coupled pathogen-recognition receptor-induced synthesis of proinflammatory cytokines (IL-12 and TNF-alpha) from DCs by hepatitis C virus (HCV) is a distinctive feature of a subgroup of chronically infected patients. The result is decreased CD8(+) T cell polyfunctional capacities (production of IFN-gamma, IL-2, TNF-alpha, and CD107a mobilization) that is confined to HCV specificities and that relates to the extent to which HCV inhibits DC responses in infected subjects, despite comparable plasma viral load, helper T cell environments, and inhibitory programmed death 1 receptor/ligand signals. Thus, subjects in whom pathogen-recognition receptor signaling in DCs was intact exhibited enhanced polyfunctionality (i.e., IL-2-secretion and CD107a). In addition, differences between HCV-infected patients in the ability of CD8(+) T cells to activate multiple functions in response to HCV did not apply to CD8(+) T cells specific for other immune-controlled viruses (CMV, EBV, and influenza). Our findings identify reversible virus evasion of DC-mediated innate immunity as an additional important factor that impacts the severity of polyfunctional CD8(+) T cell exhaustion during a chronic viral infection.
Rodrigue-Gervais
Ian Gaël
IG
Département de Microbiologie et Immunologie, Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Québec, Canada.
Rigsby
Hawley
H
Jouan
Loubna
L
Sauvé
Dominike
D
Sékaly
Rafick-Pierre
RP
Willems
Bernard
B
Lamarre
Daniel
D
D000954:Antigens, Surface / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D015550:Cell Degranulation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000096:biosynthesis; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D061026:Programmed Cell Death 1 Receptor; D051192:Receptors, Pattern Recognition / Q000037:antagonists & inhibitors / Q000502:physiology; D019562:Viral Load / Q000276:immunology; D014775:Virus Activation / Q000276:immunology
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D051192:Receptors, Pattern Recognition