Changes in the Ir gene controlled response phenotypes in mice of the Ap and Ak family of alleles expressing naturally occurring variant molecules.

Several wild-derived H-2 haplotype mice were recently shown by serology and tryptic peptide fingerprinting to express I-region A molecules closely related to the Ap and Ak molecules of the laboratory strains. To determine if such naturally occurring minor structural variations in the A molecule alter Ir gene-controlled responsiveness, we examined the immune responses of these strains after primary immunizations to three synthetic polypeptide antigens: G60Phe40, GLPhe9, and GAT10. Inbred strains carrying the Ap (or Aq) allele are known to be high responders to G60Phe40 and GLPhe9 but low responders to GAT10. Strains expressing the Ak allele are classified as low responders to G60Phe40 and GLPhe9, but high responders to GAT10. Of seven strains examined belonging to the Ap family, one (B10.CAS2) failed to respond to either G60Phe40 or GLPhe9 as measured by antibody production and T cell proliferation. In addition, two strains (B10.STC90 and W12A) of the Ak family were found to be of responder phenotype to GLPhe9. Both GLPhe9 responses resulted from the introduction of new E beta genes into the I region through naturally occurring intergenic recombination between A beta A alpha and E beta. All strains of mice in the Ak family proved to be of the high responder phenotype in their responses toward GAT10. These results contrast strongly with known patterns of alloreactivity against the variant Ap and Ak molecules.