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The genes controlling the immune response to the random linear terpolymers GAT and GLpro have been mapped in the Ir-1A or Ir-1B subregions with five lines of H-2-s/H-2-a recombinant mice. The I region also contains a third subregion, I-C, which codes for a lymphocyte-activating determinant, Lad2, controlling mixed lymphocyte reactivity. The mixed lymphocyte responses associated with I-C region disparity are compared with the stimulation noted with other H-2 region differences. Unidirectional lymphocyte activitation was associated with the Lad2 determinants in selected combinations.

The immunization of selected congenic strains and hybrids against the Ea-2.1 cellular alloantigen of the mouse demonstrated that the hammagglutinating antibody response to Ea-2.1 is regulated by a gene or genes associated with the H-2 gene complex. H-2r and H-2b are, respectively, responder and non-responder haplotypes.

The ability of various B10 congenic resistant strains to respond to the alloantigen H-2.2 was tested. High and low antibody-producing strains were distinguished by their anti-H-2.2 hemagglutinating respones. However, these strains do not differ in their ability to respond to these antigenic differences in the mixed lymphocyte culture. The humoral response to the H-2.2 alloantigen was shown to be controlled by two interacting genes localized within the H-2 complex. Thus, F1 hybrids prepared between parental low responder strains could yield high level immune responses. In addition, strains bearing recombinant H-2 haplotypes were used to map the two distinct genes controlling the immune response. The alleles at each locus were shown to be highly polymorphic as evidenced by the asymmetric complementation patterns observed. The restricted interactions of specific alleles was termed coupled complementation. The significance of the results in the terms of mechanisms of Ir gene control are discussed.

Two H-2-linked autosomal dominant immune response (Ir) genes Ir-IgG and Ir-IgA were demonstrated to be at separate loci. Ir-IgG controls the immune response to IgG (gamma2a) myeloma proteins and Ir-IgA the immune response to IgA meyloma proteins. Both genes are associated with the H-2K region specificities of the H-2 chromosome, specifically Ir-IgG with H-2(b) and Ir-IgA with H-2(a). Different recombinants derived from H-2(a)/H-2(b) crossovers were examined for their immune responsiveness to BALB/c IgG (gamma2a) and IgA myeloma proteins. B10 (H-2(b)) parental type responded only to IgG; B10.A (H-2(a)) responded only to IgA. All the recombinants except for B10.A (4R) responded to either IgG or IgA. B10.A (4R), however, responded to both IgG and IgA. This indicated that the crossover event giving rise to B10.A (4R) occurred between the Ir-IgG and Ir-IgA loci.

Eleven strains of mice bearing recombinant H-2 chromosomes derived from known crossover events between known H-2 types were immunized with a series of branched, multichain, synthetic polypeptide antigens [(T,G)-A--L, (H,G)-A--L, and (Phe,G)-A--L]. Results with nine of the eleven H-2 recombinants indicated that the gene(s) controlling immune response to these synthetic polypeptides (Ir-1) is on the centromeric or H-2K part of the recombinant H-2 chromosome. Results with two of the eleven recombinant H-2 chromosomes indicated that Ir-1 was on the telomeric or H-2D part of the recombinant H-2 chromosome. Both of these recombinants were derived from crossovers between the H-2K locus and the Ss-Slp locus near the center of the H-2 region. One of these recombinants, H-2(y), was derived from a known single crossover event. These results indicate that Ir-1 lies near the center of the H-2 region between the H-2K locus and the Ss-Slp locus. The results of a four-point linkage test were consistent with these results. In 484 offspring of a cross designed to detect recombinants between H-2 and Ir-1, only two putative recombinants were detected. Both of these recombinants were confirmed by progeny testing. Extensive analysis of one of them has shown that the crossover event occurred within the H-2 region. (Testing of the second recombinant is currently under way.) Thus, in the linkage test, recombinants between H-2 and Ir-1 are in fact intra-H-2 crossovers. These results permit assignment of Ir-1 to a position between the H-2K locus and the Ss-Slp locus.