Donald W. Bailey

Genetics of histocompatibility in mice

The H-Y antigen and minor H antigens defined by eight C57BL/6By (B6) congenic mouse strains were studied for their distribution among 13 different tissues. Antigen expression was detected by implanting B6 recipients with organ fragments from congenic strain donors that had been previously grafted with B6 bone marrow to minimize the number of allogeneic passenger leukocytes. Successfully immunized recipients were identified by the enlargement of their popliteal lymph nodes following footpad challenge with spleen cells of the donor type. No two strains had identical patterns of expression of their distinguishing antigens. The data provide evidence for differences in levels of minor H-antigen expression among different tissues.

Immunodominance in the immune response to “multiple” histocompatibility antigens

Cytotoxic effector T cells putatively specific for multiple non-H-2 histocompatibility (H) antigens were generated by immunizing and boosting C57BL/6 and B6.C-H-2dmice with BALB.B and BALB/c stimulator cells, respectively. The generated effectors were tested for cell-mediated lympholysis on a panel of targets whose BALB/c-derived non-H-2 H antigens were donated by CXB recombinant inbred mice. The spectrum of reactivity of cytotoxic effector T cells with CXB targets demonstrated that the effectors did not recognize multiple H antigens but rather preferentially recognized a single immunodominant non-H-2 H antigen. The identity of the immunodominant H antigen was determined by the H-2 genotype of the stimulator cells when (B6 × B6.C-H-2d)F1 cytotoxic effectors were tested. These observations indicate that despite the fact that responders were challenged with more than 40 individual non-H-2 H antigens, they preferentially responded to a single immunodominant antigen.

Effect of mouse genotype on interferon production. I. Lines congenic at the If-1 locus.

The level of circulating Interferon induced in mice by Newcastle disease virus is controlled by a single codominant locus,If-1, with two alleles,If-1l for low andIf-1h for high production. This locus is linked to the histocompatibility locusH-28. Of three C57BL/6By lines congenic for the BALB/cBy allele atH-28, two are carrying the BALB/cBy allele and one, the C57BL/6By allele atIf-1. Thus, mouse strains that are genetically very similar but different in their production of NDV-induced circulating Interferon now are available.

A locus affecting circulating interferon levels induced by mouse mammary tumour virus.

Summary Mendelian analysis, combined with the use of recombinant inbred strains, has revealed the existence in the mouse of a locus with a quantitative effect on circulating interferon levels induced by mouse mammary tumour virus. This locus segregates independently from the locus that affects NDV-induced interferon levels (If-1) and has been tentatively designated as If-2.

Effect of mouse genotype on interferon production. III. Expression of If-1 by peritoneal macrophages in vitro.

Upon induction with Newcastle disease virus, peritoneal macrophages derived from C57BL/6 mice produced ten times as much interferon as macrophages derived from BALB/c mice. This suggested that the alleles of theIf-1 locus are expressed in vitro by these cells. Further evidence for this was obtained by studying interferon production by peritoneal macrophages derived from seven recombinant inbred and one congenic line: in each case there was complete correlation between in vivo and in vitro phenotype: macrophages fromIf-1l mice were low producers in vitro, and macrophages fromIf-1h mice were high producers in vitro.

Genetics of histocompatibility in mice. II. Survey for interactions between minor (non-H-2) antigens by skin grafting.

Twenty-five congenic mouse strains differing at distinguishable minor (non-H−2) histocompatibility loci were paired in 71 different combinations. F1 offspring were used as skin-graft donors for more than 4000 recipients to test whether immune responses to parental strain antigens were statistically independent. Thirty-four (48 percent) of the 71 combinations were predicted adequately by an independent response hypothesis. A simple additive model was consistent with 39 (55 percent) of the observed responses, although 18 of these were among those in agreement with the independent hypothesis. A synergistic response faster than that predicted by either the independent or additive response model was seen in 12 (17 percent) of the combinations. The remaining 5 percent were not well described by any of these models. No strain was represented with unusual frequency among those involved in synergistic interactions.

Genes on different chromosomes influence the antibody response to bacterial antigens.

B6.C congenic strains of mice, possessing histocompatibility (H) alleles from high responding BALB/cBy (C) mice on the genetic background of low responding C57BL/6By (B6) mice, were assayed for their ability to make an antibody response to Type III pneumococcal polysaccharide (SSS-III) and the α(1→3) epitope of bacterial (Leuconostoc) dextran B-1355. The results affirmed that the antibody response to SSS-III is multigenic and that genes making a positive contribution to responsiveness are located on different chromosomes, i. e., chromosomes 1, 3, 4, 5, and 9. At least one other gene also influences responsiveness to SSS-III; it is linked to the H-17 locus, which has not yet been assigned to a specific chromosome. Genes on chromosomes 1, 4, and 5 influence the magnitude of the antibody response to dextran B-1355. Some of these genes may be antigen-specific in their mode of action; however, others may not since they appear to exert a positive influence on the antibody response to both SSS-III and dextran B-1355.

Interaction of H-2Db with mutant histocompatibility gene H (KH-11) in the mouse.

The detectable presence ofH(KH-11)b, a mutant non-H-2 histocompatibility gene, was previously shown to depend upon the simultaneous presence, in the skin-graft donor, of both the mutant gene and theH-2b haplotype. The experiments reported here demonstrate thatH-2Db is the essential element ofH-2b for this interaction. Of twoH-2Db histocompatibility mutations,H-2bm13 can replaceH-2Db in this interaction, butH-2ibm14 cannot.

Genetic mapping and immunogenetic characterization of the H-2fb mutation in the mouse.

Rejection of tailskin grafts exchanged between two male hybrids of the cross B10.M × B10.RIII(71NS) revealed a mutation in theH-2f haplotype from the B10.M congenic line. Complementation studies with skin grafting and cell-mediated lympholysis showed the mutant, namedH-2fb, to be different from anotherH-2f mutant,H-2fa, and further, that the HH-2fb mutation occurred in theD end of theH-2 complex. Reciprocal skin grafts exchanged between mutant and normal mice were rejected. Hemagglutinating antibody reactive with B10.M cells was raised in the mutant mice. Mutant spleen cells responded weakly, but significantly, to wild-type cells in a mixed lymphocyte culture and in a graftversus-host assay, but no response was seen in the opposite direction. However, cytotoxic effector cells were generated against target cells in both directions in a cell-mediated lympholysis assay.