title: Endogenous viral antigen processing generates peptide-specific MHC class I cell-surface clusters.
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.
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Lu
authors.forename: James S
authors.initials: JS
authors.lastname: Gibbs
authors.forename: Heather D
authors.initials: HD
authors.lastname: Hickman
authors.forename: Alexandre
authors.initials: A
authors.lastname: David
authors.forename: Brian P
authors.initials: BP
authors.lastname: Dolan
authors.forename: Yetao
authors.initials: Y
authors.lastname: Jin
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
authors.forename: Jack R
authors.initials: JR
authors.lastname: Bennink
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
authors.forename: Rajat
authors.initials: R
authors.lastname: Varma
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000378:metabolism; D000956:Antigens, Viral / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D051379:Mice; D010455:Peptides / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D001613:beta 2-Microglobulin; D046988:Proteasome Endopeptidase Complex