Cross-presentation by intercellular peptide transfer through gap junctions.
Major histocompatibility complex (MHC) class I molecules present peptides that are derived from endogenous proteins. These antigens can also be transferred to professional antigen-presenting cells in a process called cross-presentation, which precedes initiation of a proper T-cell response; but exactly how they do this is unclear. We tested whether peptides can be transferred directly from the cytoplasm of one cell into the cytoplasm of its neighbour through gap junctions. Here we show that peptides with a relative molecular mass of up to approximately 1,800 diffuse intercellularly through gap junctions unless a three-dimensional structure is imposed. This intercellular peptide transfer causes cytotoxic T-cell recognition of adjacent, innocent bystander cells as well as activated monocytes. Gap-junction-mediated peptide transfer is restricted to a few coupling cells owing to the high cytosolic peptidase activity. We present a mechanism of antigen acquisition for cross-presentation that couples the antigen presentation system of two adjacent cells and is lost in most tumours: gap-junction-mediated intercellular peptide coupling for presentation by bystander MHC class I molecules and transfer to professional antigen presenting cells for cross-priming.
Neijssen
Joost
J
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. J.Neefjes@nki.nl
Herberts
Carla
C
Drijfhout
Jan Wouter
JW
Reits
Eric
E
Janssen
Lennert
L
Neefjes
Jacques
J
D017951:Antigen Presentation / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D024201:Bystander Effect / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology; D004058:Diffusion; D005452:Fluoresceins / Q000378:metabolism; D017629:Gap Junctions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D008970:Molecular Weight; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D009975:Orthomyxoviridae / Q000276:immunology; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D021381:Protein Transport; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*
D000956:Antigens, Viral; D018031:Connexin 43; D005452:Fluoresceins; D015789:HLA-A2 Antigen; D010455:Peptides; D010447:Peptide Hydrolases; C007740:fluorexon