T cell costimulation by the hepatitis C virus envelope protein E2 binding to CD81 is mediated by Lck

Eur J Immunol. 2003 Feb;33(2):455-64. doi: 10.1002/immu.200310021.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / physiology*
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cyclodextrins / pharmacology
  • Hepacivirus / immunology*
  • Humans
  • Jurkat Cells / drug effects
  • Jurkat Cells / immunology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / deficiency
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology*
  • Membrane Microdomains / enzymology
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Neoplasm Proteins / physiology
  • Phosphorylation
  • Protein Processing, Post-Translational / physiology*
  • Receptor-CD3 Complex, Antigen, T-Cell / physiology
  • Receptors, Antigen, T-Cell / metabolism
  • Tetraspanin 28
  • Viral Envelope Proteins / immunology*
  • Viral Envelope Proteins / metabolism
  • Viral Envelope Proteins / pharmacology
  • beta-Cyclodextrins*


  • Antigens, CD
  • CD81 protein, human
  • Cyclodextrins
  • Membrane Proteins
  • Neoplasm Proteins
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell
  • Tetraspanin 28
  • Viral Envelope Proteins
  • antigen T cell receptor, zeta chain
  • beta-Cyclodextrins
  • methyl-beta-cyclodextrin
  • glycoprotein E2, Hepatitis C virus
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)