Molecular immunology of allograft rejection: insights from MHC mutants and crystal structure.

The molecular mechanisms of allograft recognition and rejection are not defined. Mice with mutations in the b allele of the H-2 K major histocompatibility complex (MHC) molecule and nonmutant parents reject skin grafts from each other. The amino acid sequences of the normal and mutant alleles are known and may be mapped on the crystal structure of the MHC molecule that has been worked out for HLA-A2. If we assume that mouse and human class I molecules are similar, these mutations may provide insight into the molecular basis of graft rejection. Mouse H-2 Kb mutants include one to four amino acid substitutions in the alpha helices that form the putative antigen-binding groove or in the beta-pleated sheets that form its floor. Alpha helical mutations have been identified with substituted residues oriented into the binding site or out away from the binding groove where they could interact with the T-cell receptor. Mutations in the beta sheets have substitutions oriented into the binding site. Certain groups of mutants with shared amino acid substitutions at some residues have other changes not shared and not adjacent to the binding site or accessible to the T-cell receptor. These mice do not reject reciprocal grafts. These observations suggest that the intact antigen binding site is important in allograft recognition and that foreign MHC molecules are not necessarily processed like other antigens and presented to the host immune system to initiate the rejection response. Foreign MHC, subtly different from host MHC, may induce graft rejection because of unique peptide fragment binding or altered conformation of the foreign antigen groove, direct interaction of specific foreign residues with the T-cell receptor, or a combination of the two.