ABSTRACT
Current ideas about DM actions have been strongly influenced by studies of mutant strains expressing the H-2(b) haplotype. To evaluate DM contributions to class II activities in BALB/c mice, we generated a novel mutation at the DMa locus via embryonic stem cell technology. Unlike long-lived A(b)/class II-associated invariant chain-derived peptide (CLIP) complexes, mature A(d) and E(d) molecules are loosely occupied by class II-associated invariant chain-derived peptide and are SDS unstable. BALB/c DM mutants weakly express BP107 conformational epitopes and toxic shock syndrome toxin-1 superantigen-binding capabilities, consistent with partial occupancy by wild-type ligands. Near normal numbers of mature CD4(+) T cells fail to undergo superantigen-mediated negative selection, as judged by TCR Vbeta usage. Ag presentation assays reveal consistent differences for A(d)- and E(d)-restricted T cells. Indeed, the mutation leads to decreased peptide capture by A(d) molecules, and in striking contrast causes enhanced peptide loading by E(d) molecules. Thus, DM requirements differ for class II structural variants coexpressed under physiological conditions in the intact animal.
Subject(s)
CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Mice, Inbred BALB C/immunology , Peptides/immunology , Peptides/metabolism , Alleles , Animals , Antigen Presentation/genetics , Antigens, Differentiation, B-Lymphocyte/genetics , Antigens, Differentiation, B-Lymphocyte/metabolism , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation/genetics , Cell Differentiation/immunology , Cell Line , Clone Cells , Crosses, Genetic , Dimerization , Female , Gene Targeting , Haplotypes , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/genetics , Lymphocyte Activation/genetics , Male , Mice , Mice, Inbred BALB C/genetics , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Peptides/genetics , Protein Conformation , Sequence Deletion , Sodium Dodecyl SulfateABSTRACT
Gastric papillomas were diagnosed in flaky skin (fsn/fsn) and steel-Dickie (Sl/Sld) mutant mice but not littermate controls. Both mutants suffer from severe anemia of differing causes. Immunohistochemical screening and Southern blot analyses failed to detect any evidence of a papillomavirus in the gastric lesions. Phenotypic expression of the fsn and Sld mutant genes may play an essential role in the spontaneous development of forestomach papillomas in these mouse mutants.
