Role of metalloproteases in vaccinia virus epitope processing for transporter associated with antigen processing (TAP)-independent human leukocyte antigen (HLA)-B7 class I antigen presentation.
The transporter associated with antigen processing (TAP) translocates the viral proteolytic peptides generated by the proteasome and other proteases in the cytosol to the endoplasmic reticulum lumen. There, they complex with nascent human leukocyte antigen (HLA) class I molecules, which are subsequently recognized by the CD8(+) lymphocyte cellular response. However, individuals with nonfunctional TAP complexes or tumor or infected cells with blocked TAP molecules are able to present HLA class I ligands generated by TAP-independent processing pathways. Herein, using a TAP-independent polyclonal vaccinia virus-polyspecific CD8(+) T cell line, two conserved vaccinia-derived TAP-independent HLA-B*0702 epitopes were identified. The presentation of these epitopes in normal cells occurs via complex antigen-processing pathways involving the proteasome and/or different subsets of metalloproteinases (amino-, carboxy-, and endoproteases), which were blocked in infected cells with specific chemical inhibitors. These data support the hypothesis that the abundant cellular proteolytic systems contribute to the supply of peptides recognized by the antiviral cellular immune response, thereby facilitating immunosurveillance. These data may explain why TAP-deficient individuals live normal life spans without any increased susceptibility to viral infections.
Instituto de Salud Carlos III, Centro Nacional de Microbiología, 28220 Majadahonda (Madrid), Spain and.
Elena
E
Lorente
Instituto de Salud Carlos III, Centro Nacional de Microbiología, 28220 Majadahonda (Madrid), Spain and.
Ruth
R
García
Instituto de Salud Carlos III, Centro Nacional de Microbiología, 28220 Majadahonda (Madrid), Spain and.
Carmen
C
Mir
Instituto de Salud Carlos III, Centro Nacional de Microbiología, 28220 Majadahonda (Madrid), Spain and.
Alejandro
A
Barriga
Unité d'Immunité Cellulaire Antivirale, Département d'Immunologie, Institut Pasteur, Paris Cedex 15, France.
François A
FA
Lemonnier
Instituto de Salud Carlos III, Centro Nacional de Microbiología, 28220 Majadahonda (Madrid), Spain and.
Manuel
M
Ramos
Instituto de Salud Carlos III, Centro Nacional de Microbiología, 28220 Majadahonda (Madrid), Spain and. Electronic address: dlopez@isciii.es.
Daniel
D
López
D000818:Animals; D017951:Antigen Presentation; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015793:HLA-B7 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D045726:Metalloproteases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology; D014615:Vaccinia / Q000235:genetics / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*
D000950:Antigens, Ly; D000939:Epitopes; D015793:HLA-B7 Antigen; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D045726:Metalloproteases; D046988:Proteasome Endopeptidase Complex