title: Greatly reduced lymphoproliferation in lpr mice lacking major histocompatibility complex class I.
abstract: Mice homozygous for the lpr gene have a defect in fas (CD95), a cell surface receptor that belongs to the tumor necrosis factor receptor family and that mediates apoptosis. This genetic abnormality results in lymphoproliferation characterized by the accumulation of CD4-CD8- (double negative [DN]) T cells, autoantibody production, and background strain-dependent, end-organ disease. Our previous results suggested that major histocompatibility complex (MHC) class I may be involved in the development of DN cells. To test this hypothesis, we derived C57BL/6-lpr/lpr (B6/lpr) mice that were deficient for the beta 2-microglobulin gene (beta 2m lpr) and had no detectable class I expression. At 6 mo of age, compared with B6/lpr littermates with normal class I genes, these mice showed greatly reduced lymphadenopathy, mostly due to a dramatic decrease in the number of DN cells. Significant changes in the percentage of other T cell subsets were noted, but only gamma/delta+ T cells showed a marked increase in both percentage and absolute numbers. Analysis of T cell receptor V beta expression of the remaining DN T cells in beta 2m -lpr mice showed a shift to a CD4-like repertoire from a CD8-like repertoire in control B6/lpr mice, indicating that a small MHC class II selected DN population was unmasked in lpr mice lacking class I. We also found that the production of immunoglobulin G (IgG) autoantibodies (antichromatin and anti-single stranded DNA), total IgG and IgG2a, but not total IgM or IgM rheumatoid factor, was significantly reduced in the beta 2m -lpr mice. This work suggests that >90% of DN T cells in lpr mice are derived from the CD8 lineage and are selected on class I. However, a T cell subset selected on class II and T cells expressing gamma/delta are also affected by the lpr defect and become minor components of the aberrant DN population.
authors.affiliation: Department of Medicine/Division of Rheumatology and Immunology, University of North Carolina at Chapel Hill 27599.
authors.forename: M A
authors.initials: MA
authors.lastname: Maldonado
authors.forename: R A
authors.initials: RA
authors.lastname: Eisenberg
authors.forename: E
authors.initials: E
authors.lastname: Roper
authors.forename: P L
authors.initials: PL
authors.lastname: Cohen
authors.forename: B L
authors.initials: BL
authors.lastname: Kotzin
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics; D001323:Autoantibodies / Q000032:analysis; D001483:Base Sequence; D015704:CD4 Antigens; D016827:CD8 Antigens; D002455:Cell Division / Q000235:genetics; D003433:Crosses, Genetic; D017931:DNA Primers; D017353:Gene Deletion; D005805:Genes, MHC Class I; D007074:Immunoglobulin G / Q000276:immunology; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics; D019014:fas Receptor
chemical_list: D000954:Antigens, Surface; D001323:Autoantibodies; D015704:CD4 Antigens; D016827:CD8 Antigens; D017931:DNA Primers; D007074:Immunoglobulin G; D001613:beta 2-Microglobulin; D019014:fas Receptor