Definition of an extended MHC class II-peptide binding motif for the autoimmune disease-associated Lewis rat RT1.BL molecule

Abstract

The Lewis rat, an inbred rat strain susceptible to several well-characterized experimental autoimmune diseases, provides a good model to study peptide-mediated immunotherapy. Peptide immunotherapy focussing on the modulation of T cell responses by interfering with TCR-peptide-MHC complex formation requires the elucidation of the molecular basis of TCR-peptide-MHC interactions for an efficient design of modulatory peptides. In the Lewis rat most autoimmune-associated CD4+ T cell responses are MHC class II RT1.BL restricted. In this study, the characteristics of RT1.BL-peptide interactions were explored. A series of substitution analogs of two Lewis rat T cell epitopes was examined in a direct peptide-MHC binding assay on isolated RT1.BL molecules. Furthermore, other autoimmune-related as well as non-disease-related T cell epitopes were tested in the binding assay. This has led to the definition of an extended RT1.BL-peptide binding motif. The RT1.BL-peptide binding motif established in this study is the first described rat MHC-peptide binding motif based on direct MHC-peptide binding experiments. To predict good or intermediate RT1.BL binding peptides, T cell epitope search profiles were deduced from this motif. The motif and search profiles will greatly facilitate the prediction of modulatory peptides based on autoimmune-associated T cell epitopes and the identification of target structures in experimental autoimmune diseases in Lewis rats.

Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS

“…And indeed, all AQP4-specific T cells established so far from wildtype animals were only weakly encephalitogenic, targeted the wrong sites, and were essentially confined to the meninges, but only poorly infiltrated the CNS parenchyma [ 32 ]. To finally answer these questions, we used one model organism—Lewis rats—to raise T cell lines against all AQP4 epitopes predicted to bind to the MHC class II products (RT1.B L ) of these animals [ 40 ], and to test the encephalitogenic potential of these cells in vivo. While all of these peptides could serve as antigens to produce stable CD4 + T H 1 cell lines and were fully able to activate T cells in vitro, the vast majority of the resulting AQP4 peptide-specific T cells were only weakly or moderately encephalitogenic.…”

Heat‐shock protein T‐cell epitopes trigger a spreading regulatory control in a diversified arthritogenic T‐cell response

“…Tbe mycobacterial antigen turned out to be the hsp60 molecule (6) and the minimal-length A2b epitope was defined to be the 180-188 sequence. In other words, the dominant antigen present in mycobacteria in AA in Lewis rats was found to be a critical antigen leading to development of the disease itself Recently, a renewed analysis based on Lewis RTl-B MHC binding motifs (7) and prediction of A2b T-cell receptor contact residues of 18 0- Despite an extensive degree of sequence conservation between the mycobacterial bsp60 molecule and its mammalian bomologuerat hsp60, the 180-188 sequence was not in a conserved part of the molecule. Therefore, it was not likely that tbe self-hsp bomologue was the target structure for arthritogenic A2b.…”

MHC Class II Isotype- and Allele-Specific Attenuation of Experimental Autoimmune Encephalomyelitis

“…Little is known about the structural characteristics of rat MHC class II molecules. Currently, only the RT1.B l ligand-binding motif, an HLA-DQ-like molecule of the LEW (RT1 l ) rat, has been described (12,13). Combinatorial peptide libraries have been successfully applied in the past to examine different aspects of MHC class I and II molecule interactions with peptide (14,15).…”