Differential recognition of a retinal autoantigen peptide and its variants by rat T cells in vitro and in vivo.
Previously we have described the role of two 14mer peptides in autoimmune uveitis, PDSAg from the retinal autoantigen S-antigen (S-Ag) and B27PD from the sequence of disease-associated HLA-B molecules, which show antigenic mimicry. The retinal peptide gave rise to severe uveitis in the Lewis rat model of experimental autoimmune uveitis (EAU) and was effective in inducing oral tolerance, while the HLA peptide B27PD caused only mild disease, but it was at least equally effective in preventing uveitis by oral tolerance. Here, we further defined the major T cell epitopes on both peptides responsible for the different functions. For this purpose we tested C- and N-terminal truncations, and chimeras consisting of amino acid sequences of both peptides in vitro and in vivo. We were able to determine the motif for binding to Lewis rat MHC class II as well as those amino acids important for recognition by T cells specific for the retinal peptide. The minimal MHC-binding nonamer peptide of PDSAg was not recognized by TCR, and we also found striking differences of T cell recognition in vitro and in vivo. The ability to induce oral tolerance was not closely correlated with uveitogenicity or with strong binding to MHC class II molecules. Our data furthermore demonstrate the importance of specific and exact trimming of peptides to be presented on MHC class II, suggesting that the presentation of cryptic epitopes is favored or prevented by existence of multiple MHC-binding motifs within a certain amino acid sequence, which can result in different or altered T cell reactions.
Wildner
Gerhild
G
Section of Immunobiology, Department of Ophthalmology, Ludwig-Maximilians-University, Mathildenstrasse 8, 80336 Munich, Germany. Gerhild.Wildner@ak-i.med.uni-muenchen.de
Diedrichs-Möhring
Maria
M
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D019393:Arrestin / Q000737:chemistry / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001667:Binding, Competitive; D002478:Cells, Cultured / Q000737:chemistry / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D005260:Female; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007633:Keratins / Q000737:chemistry / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000502:physiology; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology*
D019393:Arrestin; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006649:Histocompatibility Antigens; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; C038353:histocompatibility antigens RT, rat; D007633:Keratins