Strong alloantigenicity of the alpha-helices residues of the MHC class I molecule.
To evaluate the role of single residues of a MHC class I molecule in the induction of a primary allogeneic response, we have tested the ability of various point mutants (of the alpha-helices or beta-sheet of the alpha1 and alpha2 domains) of the Kd molecule to induce a primary cytotoxic T cell response in mice carrying the wild-type molecule. For that, we have used an in vivo model in which cells expressing mutant molecules were injected into the hind footpads of mice carrying wild-type Kd, and the recipient graft-draining popliteal lymph nodes were tested for the presence of alloreactive CTL. Under these experimental conditions, only 7 of the 25 mutant Kd molecules induced a primary allogeneic response. All of these mutations (positions 62, 65, 69, 72, 155, 163, 166) concern residues of the alpha-helices, demonstrating that very small variances from self in a class I molecule, located outside the peptide-binding groove, can be antigenic. To determine the peptide requirements for the generation of a primary allogeneic response, we have analyzed the repertoire of peptides selected by individual mutant molecules shown to be able or unable to induce a CTL response. No correlation was observed between the peptidic make-up presented by a given mutant and its capacity to induce a primary allogeneic response. On the whole, our data point to the alloantigenicity of potentially TCR-contacting surface residues of the MHC class I molecules.
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Mouse Immunogenetics, U462, Institut National de la Santé et de la Recherche Médicale, Institute of Hematology, Paris, France.
Reboul
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Abastado
J P
JP
Kourilsky
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P
Sigaux
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Pla
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D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000596:Amino Acids / Q000235:genetics / Q000276:immunology*; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005347:Fibroblasts / Q000637:transplantation; D006183:H-2 Antigens / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D007279:Injections, Subcutaneous; D007519:Isoantigens / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017433:Protein Structure, Secondary; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection / Q000276:immunology
D000596:Amino Acids; D006183:H-2 Antigens; D007519:Isoantigens; D010446:Peptide Fragments