Folding of matrix metalloproteinase-2 prevents endogenous generation of MHC class-I restricted epitope.
BACKGROUND
We previously demonstrated that the matrix metalloproteinase-2 (MMP-2) contained an antigenic peptide recognized by a CD8 T cell clone in the HLA-A*0201 context. The presentation of this peptide on class I molecules by human melanoma cells required a cross-presentation mechanism. Surprisingly, the classical endogenous processing pathway did not process this MMP-2 epitope.


RESULTS
By PCR directed mutagenesis we showed that disruption of a single disulfide bond induced MMP-2 epitope presentation. By Pulse-Chase experiment, we demonstrated that disulfide bonds stabilized MMP-2 and impeded its degradation. Finally, using drugs, we documented that mutated MMP-2 epitope presentation used the proteasome and retrotranslocation complex.


CONCLUSIONS
These data appear crucial to us since they established the existence of a new inhibitory mechanism for the generation of a T cell epitope. In spite of MMP-2 classified as a self-antigen, the fact that cross-presentation is the only way to present this MMP-2 epitope underlines the importance to target this type of antigen in immunotherapy protocols.
Renaud
Virginie
V
Institut National de la Santé et de la Recherche Médicale, UMR 892, Nantes, France.
Godefroy
Emmanuelle
E
Larrieu
Pierre
P
Fleury
Fabrice
F
Jotereau
Francine
F
Guilloux
Yannick
Y
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004591:Electrophoresis, Polyacrylamide Gel; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000276:immunology*
D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D020778:Matrix Metalloproteinase 2