GREATLY REDUCED LYMPHOPROLIFERATION IN LPR MICE LACKING MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I

Mice homozygous for the lpr gene have a defect in fas (CD95), a cell s urface receptor that belongs to the tumor necrosis factor receptor fam ily and that mediates apoptosis. This genetic abnormality results in l ymphoproliferation 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 t hat 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)-microglob ulin gene (beta(2)m(-)lpr) and had no detectable class I expression. A t 6 mo of age, compared with B6/lpr littermates with normal class I ge nes, 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/delt a(+) T cells showed a marked increase in both percentage and absolute numbers. Analysis of T cell receptor V beta expression of the remainin g DN T cells in beta(2)m-lpr mice showed a shift to a CD4-like reperto ire 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), to tal IgG and IgG2a, but not total IgM or IgM rheumatoid factor, was sig nificantly reduced in the beta(2)m(-)lpr mice. This work suggests that >90% of DN T cells in lpr mice are derived from the CD8 lineage and a re 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.