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Strong Alloantigenicity of the -Helices Residues of the MHC Class I Molecule¹

Ghada Noun^*, Murielle Reboul^*, Jean-Pierre Abastado, Philippe Kourilsky, François Sigaux^* and Marika Pla^2,*

^* Mouse Immunogenetics, U462, Institut National de la Santé et de la Recherche Médicale, Institute of Hematology, Paris, France; and U277, Institut National de la Santé et de la Recherche Médicale, Pasteur Institute, Paris, France

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 -helices or ß-sheet of the ₁ and ₂ domains) of the K^d 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 K^d, 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 K^d molecules induced a primary allogeneic response. All of these mutations (positions 62, 65, 69, 72, 155, 163, 166) concern residues of the -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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