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 ill the induction of a primary allogeneic response, we have tested the abi lity of various point mutants (of the alpha-helices or beta-sheet of t he alpha(1) and alpha(2 )domains) of the K-d molecule to induce a prim ary cytotoxic T cell response in mice carrying the wild-type molecule. For that, we have used an in vivo model in which cells expressing mut ant molecules were injected into the hind footpads of mice carrying wi ld-type Kd, and the recipient graft-draining popliteal lymph nodes wer e tested for the presence of alloreactive CTL, Under these experimenta l 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 alpha-helices, demonstrating t hat very small variances from self in a class I molecule, located outs ide the peptide-binding groove, can be antigenic, To determine the pep tide requirements for the generation of a primary allogeneic response, we have analyzed the repertoire of peptides selected by individual mu tant 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 T CR-contacting surface residues of the MHC class I molecules.