title: Allogeneic core amino acids of an immunodominant allopeptide are important for MHC binding and TCR recognition.
abstract: The indirect alloimmune response seems to be restricted to a few dominant major histocompatibility complex (MHC)-derived peptides responsible for T-cell activation in allograft rejection. The molecular mechanisms of indirect T-cell activation have been studied using peptide analogues derived from the dominant allopeptide in vitro, whereas the in vivo effects of peptide analogues have not been well characterized yet. In the present study, we generated allochimeric peptide analogues by replacing the three allogeneic amino acids 5L, 9L, and 10T in the sequence of the dominant MHC class I allopeptide P1. These allochimeric peptide analogues were used to define the allogeneic amino acids critical for the MHC binding and TCR recognition. We found that position 5 (5L) of the dominant allopeptide acts as an MHC-binding residue, while the other two allogeneic positions, 9 and 10, are important for the T-cell receptor (TCR) recognition. A peptide containing the MHC-binding residue 5L, as the only different amino acid between donor (RT1.A(u)) and recipient (RT1.A(l)) sequences, did not induce proliferation of lymph node cells primed with the dominant peptide and prevented dominant peptide-induced acceleration of allograft rejection. Identification of MHC and TCR contact residues should facilitate the development of antigen-specific therapies to inhibit or regulate the indirect alloimmune response.
authors.affiliation: Department of Surgery, University of Würzburg, Würzburg, Germany.
authors.forename: Ana Gabriela
authors.initials: AG
authors.lastname: Sitaru
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Timmermann
authors.forename: Karin
authors.initials: K
authors.lastname: Ulrichs
authors.forename: Christoph
authors.initials: C
authors.lastname: Otto
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001667:Binding, Competitive; D016207:Cytokines / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D006649:Histocompatibility Antigens / Q000737:chemistry* / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006789:Host vs Graft Reaction / Q000276:immunology; D016056:Immunodominant Epitopes / Q000737:chemistry* / Q000276:immunology; D007519:Isoantigens / Q000737:chemistry* / Q000276:immunology*; D007930:Leucine / Q000737:chemistry / Q000276:immunology; D010449:Peptide Mapping; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D006649:Histocompatibility Antigens; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D007519:Isoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C038353:histocompatibility antigens RT, rat; D007930:Leucine