Molecular Mimicry of Human Cytochrome P450 by Hepatitis C Virus at the Level of Cytotoxic T Cell Recognition

Kammer, Andreas R.; van der Burg, Sjoerd H.; Grabscheid, Benno; Hunziker, Isabelle P.; Kwappenberg, Kitty M.C.; Reichen, Jürg; Melief, Cornelis J.M.; Cerny, Andreas

In our study we could not induce CTLs with the CYPderived self-peptides, although the same self-peptides were rec- ognized by CTLs induced with the HCV core 178 epitope. This indicates different T cell activation properties of the selfepitopes compared with the HCV peptide as described for altered peptide ligands (APLs), which are analogues of immunogenic peptides with amino acid substitutions inducing different effects in CTLs. APLs can act as agonists leading to full activation of T cells, partial agonists inducing only a reduced T cell response, or even antagonists inhibiting a response against the unaltered immunogenic epitope (33, 34) . The molecular mechanisms of APL-induced partial T cell activation are still a matter of debate (35) . Complexes of the native ligand or APLs with MHC molecules binding to the TCR can induce different intracellular signals in T cells (36) (37) (38) , either by different oligomerization of necessary molecules (CD3, CD8, or other molecules), or by a failure of the APL to induce a required conformational change in the TCR. Other studies state that the level of T cell activation is dependent on the number of TCRs triggered in a process of serial engagement of many TCRs by a few peptide-MHC complexes, allowing a single CTL to generate different biological responses (39) . Although specific cytotoxicity is already detectable at very low peptide concentrations, IFN-␥ production and proliferation require higher concentrations corresponding to higher numbers of TCRs being triggered (40) . This is in accordance with the finding that the immunogenicity of antigenic peptides strongly correlates with the stability of MHC-peptide complexes formed (28) , indicating that a high number and a high stability of MHC-peptide complexes is essential to trigger a sufficient number of TCRs to fully activate naive T cells. Despite this, the final effect of affinity differences or kinetic changes on the multimolecular interactions during antigen recognition cannot be predicted, as there is no strict correlation between functional activity of the various peptides and their MHC binding efficiency and the affinity of the MHC-peptide complexes for the TCR (31) .