A retro-inverso analog mimics the cognate peptide epitope of a CD4+ T cell clone.
Synthetic analogs of peptide epitopes may activate specific T helper cells, antagonize their antigen receptors, or block recognition by competing for major histocompatibility complex (MHC) class II binding sites. Rationally designed peptides may therefore prove useful as vaccines and for treatment of autoimmune diseases and allergies mediated by CD4+ T cells. However, their susceptibility to proteolytic degradation limits the applicability of conventional peptides in vivo. By contrast, retro-inverso analogs, in which a native sequence is substituted with D-amino acids linked with a reversed backbone, resist proteolysis and still maintain the side chain topology of the corresponding natural peptide. We report here that an end group-modified retro-inverso analog of the IgG2ab heavy chain allopeptide determinant gamma 2ab 435-447 was recognized by an I-Ad-restricted, gamma 2ab 435-447-reactive T cell clone. The pseudopeptide elicited near-maximal interleukin-2 responses, although 300-fold higher concentrations were needed than the native determinant. The weaker antigenicity of the retro-inverso analog could be fully accounted for by an impaired I-Ad binding capacity, which might reflect reduced ability of the distorted main chain to form hydrogen bonds with I-Ad. Glycine substitution at the residue corresponding to the first primary anchor (P1) of the native peptide abrogated I-Ad binding and antigenicity of the retro-inverso analog. Thus, the pseudopeptide resembled the native determinant with respect to orientation in the class II binding site, configuration of the epitopic side chains, and the constraints that governed the interactions between a major anchoring side chain and I-Ad. In conclusion, proteolytically resistant compounds with predefined capacity to interact with MHC class II allelic products and T cell antigen receptors may be designed by retro-inverso modification of native determinants.
Bartnes
K
K
Department of Immunology, University of Tromsø, School of Medicine, Norway.
Hannestad
K
K
Guichard
G
G
Briand
J P
JP
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D002999:Clone Cells; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000737:chemistry / Q000276:immunology
D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D010455:Peptides