title: TCR-like antibodies distinguish conformational and functional differences in two- versus four-domain auto reactive MHC class II-peptide complexes.
abstract: Antigen-presenting cell-associated four-domain MHC class II (MHC-II) molecules play a central role in activating autoreactive CD4(+) T cells involved in multiple sclerosis (MS) and type 1 diabetes (T1D). In contrast, two-domain MHC-II structures with the same covalently attached self-peptide (recombinant T-cell receptor ligands (RTLs)) can regulate pathogenic CD4(+) T cells and reverse clinical signs of experimental autoimmune diseases. RTL1000, which is composed of the β1α1 domains of human leukocyte antigen (HLA)-DR2 linked to the encephalitogenic human myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, was recently shown to be safe and well tolerated in a phase I clinical trial in MS. To evaluate the opposing biological effects of four- versus two-domain MHC-II structures, we screened phage Fab antibodies (Abs) for the neutralizing activity of RTL1000. Five different TCR-like Abs were identified that could distinguish between the two- versus four-domain MHC-peptide complexes while the cognate TCR was unable to make such a distinction. Moreover, Fab detection of native two-domain HLA-DR structures in human plasma implies that there are naturally occurring regulatory MHC-peptide complexes. These results demonstrate for the first time distinct conformational determinants characteristic of activating versus tolerogenic MHC-peptide complexes involved in human autoimmunity.
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Dahan
authors.forename: Moran
authors.initials: M
authors.lastname: Tabul
authors.forename: Yuan K
authors.initials: YK
authors.lastname: Chou
authors.forename: Roberto
authors.initials: R
authors.lastname: Meza-Romero
authors.forename: Shayne
authors.initials: S
authors.lastname: Andrew
authors.forename: Adolph J
authors.initials: AJ
authors.lastname: Ferro
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Yoram
authors.initials: Y
authors.lastname: Reiter
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006023:Glycoproteins; D015802:HLA-DR2 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D006023:Glycoproteins; D015802:HLA-DR2 Antigen; D000949:Histocompatibility Antigens Class II; D007140:Immunoglobulin Fab Fragments; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C542328:RTL1000 protein; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55)