Generation of an immunodominant CTL epitope is affected by proteasome subunit composition and stability of the antigenic protein.

Abstract

Generation of the HLA-A0201 (A2) influenza Matrix 58-66 epitope contained within the full-length Matrix protein is impaired in cells lacking the proteasome subunits low molecular protein 2 (LMP2) and LMP7. This Ag presentation block can be relieved by transfecting the wild-type LMP7 cDNA into LMP7-deficient cells. A mutated form of LMP7, lacking the two threonines at the catalytic active site, was equally capable of relieving the block in presentation of the influenza Matrix A2 epitope. These observations were extended by analyzing whether modification of the influenza Matrix protein could overcome the block in presentation of the A2 Matrix epitope. Expression of either a rapidly degraded form of the full-length Matrix protein or shorter Matrix fragments led to an efficient presentation of the A2 influenza Matrix epitope by LMP7-negative cells. These findings demonstrate two main points: 1) LMP7 incorporation into the proteasome is of greater importance for the generation of the influenza A2 Matrix epitope than the presence of the LMP7's catalytic site; and 2) the interplay between cytosolic proteases and stability of target proteins is of importance in optimization of Ag presentation. These observations may have relevance to the immunodominance of tumor and viral epitopes and raise the possibility that generation of shorter protein fragments could be a mechanism to ensure optimal Ag presentation by cells expressing low levels of LMP7.

• Authors: U Gileadi, H T Moins-Teisserenc, I Correa, B L Booth Jr, P R Dunbar, A K Sewell, J Trowsdale, R E Phillips, V Cerundolo
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 163 Issue 11 Pg. 6045-52 (Dec 01 1999) ISSN: 0022-1767 [Print] United States
• PMID: 10570292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunodominant Epitopes
• Multienzyme Complexes
• Peptide Fragments
• Proteins
• Viral Matrix Proteins
• influenza virus membrane protein (58-66)
• LMP-2 protein
• Cysteine Endopeptidases
• LMP7 protein
• Proteasome Endopeptidase Complex

Topics

• Antigen Presentation
• Cysteine Endopeptidases (metabolism)
• Half-Life
• Immunodominant Epitopes
• Influenza A virus (immunology)
• Multienzyme Complexes (metabolism)
• Peptide Fragments (immunology, metabolism)
• Proteasome Endopeptidase Complex
• Protein Processing, Post-Translational
• Proteins (genetics, metabolism)
• Viral Matrix Proteins (immunology, metabolism)