Immunogenetics of resistance to Friend murine leukemia virus in mice

Abstract

Mice homozygous for the H-2{dollar}\sp{lcub}d{rcub}{dollar} haplotype at the major histocompatibility complex are markedly more susceptible to erythroleukemia induction by the Friend isolate of murine leukemia retrovirus (FV) than congenic mice homozygous for the H-2{dollar}\sp{lcub}b{rcub}{dollar} haplotype. The resistance conferred by the H-2{dollar}\sp{lcub}b{rcub}{dollar} haplotype is recessive, since heterozygous F{dollar}\sb1{dollar} mice are as susceptible as parental strain H-2{dollar}\sp{lcub}d{rcub}{dollar} homozygotes. In an attempt to more precisely map the genes responsible for resistance and susceptibility we have used congenic mice with recombinant as well as mutant H-2 haplotypes. We have also sought the mechanism responsible for the in vivo observations using in vitro immunologic assays. These studies have shown that the resistance associated with the H-2{dollar}\sp{lcub}b{rcub}{dollar} haplotype is tightly linked to the class I MHC molecule L{dollar}\sp{lcub}\rm b{rcub}{dollar} (also called D{dollar}\sp{lcub}\rm b{rcub}{dollar}), the only class I molecule encoded in the D region of H-2{dollar}\sp{lcub}b{rcub}{dollar}. However, {dollar}L\sp{lcub}b{rcub}{dollar}-associated resistance is not an intrinsically recessive trait; it is suppressed by the D{dollar}\sp{lcub}\rm d{rcub}{dollar} molecule, one of five D region molecules of the H-2{dollar}\sp{lcub}d{rcub}{dollar} haplotype. In vitro T cell responses from {dollar}L\sp{lcub}b+{rcub}/D\sp{lcub}d+{rcub}{dollar} mice are much weaker than from {dollar}L\sp{lcub}b+{rcub}/D\sp{lcub}d-{rcub}{dollar} mice. In addition, infected target cells from {dollar}L\sp{lcub}b+{rcub}/D\sp{lcub}d+{rcub}{dollar} mice are not recognized as efficiently by L{dollar}\sp{lcub}\rm b{rcub}{dollar}-restricted FV-specific cytotoxic T lymphocytes as targets from {dollar}L\sp{lcub}b+{rcub}/D\sp{lcub}d-{rcub}{dollar} mice. These data suggest that the D{dollar}\sp{lcub}\rm d{rcub}{dollar} is interfering with the ability of the L{dollar}\sp{lcub}\rm b{rcub}{dollar} to properly present antigens to T cells, perhaps by competing for an immunodominant peptide epitope. Interestingly, transfection of the D{dollar}\sp{lcub}\rm d{rcub}{dollar} gene into an FV-induced tumor line from homozygous L{dollar}\sp{lcub}\rm b{rcub}{dollar} mice does not inhibit recognition by CTL, but does inhibit lysis by natural killer cells. Although these studies have not yet described a simple mechanism to explain the recessive nature of resistance to FV in these mice, they have clearly demonstrated that the presence of one MHC molecule can suppress immunologic resistance associated with another MHC molecule.