Processing of two latent membrane protein 1 MHC class I epitopes requires tripeptidyl peptidase II involvement.
The EBV Ag latent membrane protein 1 (LMP1) has been described as a potential target for T cell immunotherapy in EBV-related malignancies. However, only a few CD8(+) T cell epitopes are known, and the benefit of LMP1-specific T cell immunotherapy has not yet been proven. In this work, we studied the processing of the two LMP1 HLA-A02-restricted epitopes, YLLEMLRWL and YLQQNWWTL. We found that target cells endogenously expressing the native LMP1 are not recognized by CTLs specific for these epitopes because the N-terminal part of LMP1 limits the efficiency of epitope generation. We further observed that the proteasome is not required for the generation of both epitopes and that the YLLEMLRWL epitope seems to be destroyed by the proteasome, because blocking of proteasomal activities enhanced specific CTL activation. Activation of LMP1-specific CTLs could be significantly reduced after inhibition of the tripeptidyl peptidase II, suggesting a role for this peptidase in the processing of both epitopes. Taken together, our results demonstrate that the MHC class I-restricted LMP1 epitopes studied in this work are two of very few epitopes known to date to be processed proteasome independently by tripeptidyl peptidase II.
Diekmann
Jan
J
Medical Clinic und Policlinic II, Julius-Maximilian University of Wuerzburg, Wuerzburg, Germany.
Adamopoulou
Eleni
E
Beck
Olaf
O
Rauser
Georg
G
Lurati
Sarah
S
Tenzer
Stefan
S
Einsele
Hermann
H
Rammensee
Hans-Georg
HG
Schild
Hansjörg
H
Topp
Max S
MS
D000595:Amino Acid Sequence; D000626:Aminopeptidases; D017951:Antigen Presentation / Q000276:immunology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D000939:Epitopes; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D006801:Humans; D016393:Lymphoma, B-Cell / Q000821:virology*; D046988:Proteasome Endopeptidase Complex; D012697:Serine Endopeptidases / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D000939:Epitopes; D015234:HLA-A Antigens; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D014763:Viral Matrix Proteins; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D046988:Proteasome Endopeptidase Complex