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

✍ Scribed by Elisabetta Soldaini; Andreas Wack; Ugo D'Oro; Sandra Nuti; Cristina Ulivieri; Cosima T. Baldari; Sergio Abrignani

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 371 KB
• Volume: 33
• Category: Article
• ISSN: 0014-2980
• DOI: 10.1002/immu.200310021

✦ Synopsis

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‐β‐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 TCRζ 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.