Endogenous viral antigen processing generates peptide-specific MHC class I cell-surface clusters.

TitleEndogenous viral antigen processing generates peptide-specific MHC class I cell-surface clusters.
Publication TypeJournal Article
Year of Publication2012
AuthorsLu X, Gibbs JS, Hickman HD, David A, Dolan BP, Jin Y, Kranz DM, Bennink JR, Yewdell JW, Varma R
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue38
Pagination15407-12
Date Published2012 Sep 18
ISSN1091-6490
KeywordsAnimals, Antigen Presentation, Antigen-Presenting Cells, Antigens, Viral, beta 2-Microglobulin, CD8-Positive T-Lymphocytes, Cell Line, Cytoplasm, Golgi Apparatus, Histocompatibility Antigens Class I, Mice, Peptides, Proteasome Endopeptidase Complex
Abstract

Sensitivity is essential in CD8+ T-cell killing of virus-infected cells and tumor cells. Although the affinity of the T-cell receptor (TCR) for antigen is relatively low, the avidity of T cell-antigen-presenting cell interactions is greatly enhanced by increasing the valence of the interaction. It is known that TCRs cluster into protein islands after engaging their cognate antigen (peptides bound to MHC molecules). Here, we show that mouse K(b) class I molecules segregate into preformed, long-lasting (hours) clusters on the antigen-presenting cell surface based on their bound viral peptide. Peptide-specific K(b) clustering occurs when source antigens are expressed by vaccinia or vesicular stomatitis virus, either as proteasome-liberated precursors or free intracellular peptides. By contrast, K(b)-peptide complexes generated by incubating cells with synthetic peptides are extensively intermingled on the cell surface. Peptide-specific complex sorting is first detected in the Golgi complex, and compromised by removing the K(b) cytoplasmic tail. Peptide-specific clustering is associated with increased T-cell sensitivity: on a per-complex basis, endogenous SIINFEKL activates T cells more efficiently than synthetic SIINFEKL, and wild-type K(b) presents endogenous SIINFEKL more efficiently than tailless K(b). We propose that endogenous processing generates peptide-specific clusters of class I molecules to maximize the sensitivity and speed of T-cell immunosurveillance.

DOI10.1073/pnas.1208696109
Alternate JournalProc. Natl. Acad. Sci. U.S.A.