Reconstruction of a pathway of antigen processing and class II MHC peptide capture.
Endocytosed antigens are proteolytically processed and small amounts of peptides captured by class II MHC molecules. The details of antigen proteolysis, peptide capture and how destruction of T-cell epitopes is avoided are incompletely understood. Using the tetanus toxin antigen, we show that the introduction of 3-6 cleavage sites is sufficient to trigger a partially unfolded conformation able to bind to class II MHC molecules. The known locations of T-cell epitopes and protease cleavage sites predict that large domains of processed antigen (8-35 kDa) are captured under these conditions. Remarkably, when antigen is bound to the B-cell antigen receptor (BCR), processing can trigger a concerted 'hand-over' reaction whereby BCR-associated processed antigen is captured by neighbouring class II MHC molecules. Early capture of minimally processed antigen and confinement of the processing and class II MHC loading reaction to the membrane plane may improve the likelihood of T-cell epitope survival in the class II MHC pathway and may help explain the reciprocal relationships observed between B- and T-cell epitopes in many protein antigens and autoantigens.
Moss
Catherine X
CX
Division of Cell Biology & Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
Tree
Timothy I
TI
Watts
Colin
C
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000502:physiology*; D002460:Cell Line; D002850:Chromatography, Gel; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D018448:Models, Immunological; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D013744:Tetanus Toxin / Q000235:genetics / Q000378:metabolism*
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D011947:Receptors, Antigen, B-Cell; D013744:Tetanus Toxin