Is antigen processing guided by major histocompatibility complex molecules?
Major histocompatibility complex class I (MHC-1) molecules bind peptide fragments derived from cytosolic antigens, and class II (MHC-2) molecules bind fragments of proteins that enter the endocytic pathway. How peptides of the right affinity and size are generated in vivo is still the focus of intense research. Current data are consistent with the view that precursor peptides of varying length are produced in the cytosol and transported into the endoplasmic reticulum lumen where nascent MHC-1 could sample the peptides for their affinity. High-affinity peptides would form stable complexes with MHC-1, which are resistant to proteolysis by luminal enzymes; peptides unable to bind to MHC-1 presumably undergo proteolysis in the lumen. On the other hand, multiple mechanisms are probably used to load MHC-2. Some proteins denatured in the acidic and reducing environment of the endosomes most likely bind to MHC-2 through the antigen's immunodominant region, and the exposed portions of the antigen are degraded by endosomal proteases. Other antigens must first be proteolysed into peptide fragments, which compete among themselves for binding to MHC-2, whereas heat shock proteins could also contribute peptides for MHC-2 loading. Because of their respective loading modes, there is a partial correlation between the MHC-2 binding affinity of the protein fragments and their in vivo immunodominance, which may not necessarily be the case for MHC-1.
Ojcius
D M
DM
Pasteur Institute, Paris, France.
Gapin
L
L
Kanellopoulos
J M
JM
Kourilsky
P
P
D017951:Antigen Presentation; D001667:Binding, Competitive; D004705:Endocytosis; D010450:Endopeptidases / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D008954:Models, Biological; D015388:Organelles / Q000201:enzymology; D010446:Peptide Fragments / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D010450:Endopeptidases