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PMID: 11602636 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Processing of a multiple membrane spanning Epstein-Barr virus protein for CD8(+) T cell recognition reveals a proteasome-dependent, transporter associated with antigen processing-independent pathway.

The Journal of experimental medicine ·Vol. 194 ·No. 8 ·2001-10-15 ·Pages 1053-68

Lautscham G, Mayrhofer S, Taylor G, Haigh T, Leese A, Rickinson A, Blake N

Abstract

Epstein-Barr virus (EBV) latent membrane protein (LMP)2 is a multiple membrane spanning molecule which lacks ectodomains projecting into the lumen of the endoplasmic reticulum (ER). Human CD8(+) cytotoxic T lymphocytes (CTL)s recognize a number of epitopes within LMP2. Assays with epitope-specific CTLs in two different cell backgrounds lacking the transporter associated with antigen processing (TAP) consistently show that some, but not all, LMP2 epitopes are presented in a TAP-independent manner. However, unlike published examples of TAP-independent processing from endogenously expressed antigens, presentation of TAP-independent LMP2 epitopes was abrogated by inhibition of proteasomal activity. We found a clear correlation between hydrophobicity of the LMP2 epitope sequence and TAP independence, and experiments with vaccinia minigene constructs expressing cytosolic epitope peptides confirmed that these more hydrophobic peptides were selectively able to access the HLA class I pathway in TAP-negative cells. Furthermore, the TAP-independent phenotype of particular epitope sequences did not require membrane location of the source antigen since (i) TAP-independent LMP2 epitopes inserted into an EBV nuclear antigen and (ii) hydrophobic epitope sequences native to EBV nuclear antigens were both presented in TAP-negative cells. We infer that there is a proteasome-dependent, TAP-independent pathway of antigen presentation which hydrophobic epitopes can selectively access.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily B, Member 2 ATP Binding Cassette Transporter, Subfamily B, Member 3 ATP-Binding Cassette Transporters/genetics,immunology Antigen Presentation/immunology Cell Line, Transformed Cysteine Endopeptidases/immunology Cysteine Proteinase Inhibitors/pharmacology Epithelial Cells Epitope Mapping Epitopes, T-Lymphocyte/immunology HLA-A Antigens/immunology HLA-A24 Antigen HLA-B Antigens/immunology HLA-B27 Antigen/immunology HLA-B40 Antigen Herpesvirus 4, Human/immunology Humans Multienzyme Complexes/antagonists & inhibitors,immunology Nuclear Proteins/immunology Proteasome Endopeptidase Complex Signal Transduction/immunology T-Lymphocytes, Cytotoxic/immunology Tumor Cells, Cultured Viral Matrix Proteins/immunology
Chemicals
ATP Binding Cassette Transporter, Subfamily B, Member 2 ATP Binding Cassette Transporter, Subfamily B, Member 3 ATP-Binding Cassette Transporters Cysteine Proteinase Inhibitors EBV-associated membrane antigen, Epstein-Barr virus Epitopes, T-Lymphocyte HLA-A Antigens HLA-A24 Antigen HLA-B Antigens HLA-B27 Antigen HLA-B40 Antigen Multienzyme Complexes Nuclear Proteins TAP1 protein, human Viral Matrix Proteins TAP2 protein, human Cysteine Endopeptidases Proteasome Endopeptidase Complex
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Lautscham G
Cancer Research Campaign Institute for Cancer Studies and Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Mayrhofer S
Taylor G
Haigh T
Leese A
Rickinson A
Blake N
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.194.8.1053
Published
2001-10-15
Pages
1053-68
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193515
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.194.8.1053 PMC Full Text View journal details
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