title: T cell costimulation by the hepatitis C virus envelope protein E2 binding to CD81 is mediated by Lck.
abstract: Binding of the hepatitis C virus (HCV) envelope protein E2 to CD81 provides a costimulatory signal for human T cells. This phenomenon may play a role in liver damage and autoimmune manifestations associated with HCV infection. Here we show that cross-linking of CD81 by HCV E2 induced a calcium flux in T cells that depends on Lck since it was blocked by PP1 and absent in Lck-deficient Jurkat T cells. In wild-type Jurkat cells, Lck was activated by CD81 cross-linking, and CD81, like Lck, was found in lipid rafts. Indeed, the integrity of the raft compartment was required for the induction of a calcium flux by E2, since methyl-beta-cyclodextrin abolished this response. A requirement for TCR/CD3 expression was indicated by the absence of a calcium flux following E2 stimulation of TCR/CD3-deficient Jurkat cells. CD81 cross-linking increased and prolonged the anti-CD3-induced tyrosine phosphorylation of TCR1 and of other proteins, indicating that the CD81-mediated signal converges with the TCR/CD3 signaling cascade at its most upstream step. In conclusion, we propose that the costimulatory effects of HCV E2 on T cells depend on CD81 cross-linking that activates Lck through raft aggregation and thus leads to enhanced TCR signaling.
authors.affiliation: IRIS Research Center, Chiron, Siena, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soldaini
authors.forename: Andreas
authors.initials: A
authors.lastname: Wack
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
authors.forename: Sandra
authors.initials: S
authors.lastname: Nuti
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.forename: Cosima T
authors.initials: CT
authors.lastname: Baldari
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
mesh_terms: D015703:Antigens, CD / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D003505:Cyclodextrins / Q000494:pharmacology; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000172:deficiency / Q000502:physiology*; D021962:Membrane Microdomains / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D047392:beta-Cyclodextrins
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; D003505:Cyclodextrins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C054979:antigen T cell receptor, zeta chain; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C091015:glycoprotein E2, Hepatitis C virus; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)