Presentation of the Goodpasture autoantigen to CD4 T cells is influenced more by processing constraints than by HLA class II peptide binding preferences.
Class II molecules are believed to influence immune responses by selectively binding antigen-derived peptides for recognition by T cells. In Goodpasture's (anti-glomerular basement membrane) disease, autoimmunity to the NC1 domain of the alpha3-chain of type IV collagen (alpha3(IV)NC1) is strongly associated with HLA-DR15. We have examined the influence of the peptide binding preferences of DR15 molecules on the selection of alpha3(IV)NC1-derived peptides displayed bound to DR15 molecules on the surface of alpha3(IV)NC1-pulsed DR15-homozygous Epstein-Barr virus-transformed human B cells. The preferences of DR15 molecules were investigated using a panel of 24 overlapping peptides spanning the sequence of alpha3(IV)NC1. The alpha3(IV)NC1-derived peptides selected for display to T cells were determined by biochemical analysis as reported previously (Phelps, R. G., Turner, A. N., and Rees, A. J. (1996) J. Biol. Chem. 271, 18549-18553). Three nested sets of naturally presented alpha3(IV)NC1 peptides were detectable bound to DR15 molecules. Peptides representative of each nested set bound to DR15 molecules, but almost two-thirds of the alpha3(IV)NC1 peptides studied had as good or better DR15 affinity than those identified as naturally processed. Thus alpha3(IV)NC1 presentation to T cells is determined more by "processing factors" than by the preferences of relatively indiscriminate DR15 molecules. The results have important implications for the use of class II peptide binding data to aid identification of potential T cell epitopes, especially for antigens which, like alpha3(IV)NC1, contain many sequences able to bind class II molecules.
Phelps
R G
RG
Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, United Kingdom. r.phelps@abdn.ac.uk
Jones
V L
VL
Coughlan
M
M
Turner
A N
AN
Rees
A J
AJ
D000595:Amino Acid Sequence; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003094:Collagen / Q000276:immunology* / Q000378:metabolism; D024141:Collagen Type IV; D018604:Epitope Mapping; D006684:HLA-DR Antigens / Q000378:metabolism*; D059810:HLA-DR Serological Subtypes; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship
D001324:Autoantigens; D024141:Collagen Type IV; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; D010455:Peptides; C057112:type IV collagen alpha3 chain; D003094:Collagen