Chronic treatment of C3H-lpr/lpr and C3H-gld/gld mice with anti-CD8 monoclonal antibody prevents the accumulation of double negative T cells but not autoantibody production.

Abstract Mice homozygous for lpr or gld develop autoimmunity and progressive lymphoproliferative disease characterized by the accumulation of an unusual population of functionally impaired B220+, TCR-alpha/beta +, CD4-, CD8- double negative (DN) T cells. Although these cells are thymus derived and appear to have undergone thymic negative selection, the identity of their immediate precursors and the mechanisms leading to their accumulation are poorly understood. Here we investigated the role of CD8+ T cells in the development of lymphoproliferative disease and autoantibody production. We showed that treatment of C3H-Ipr or C3H-gld mice with anti-CD8 mAb beginning at 3 wk of age and continuing to 15 wk of age caused a dramatic reduction in lymphadenopathy. the change in lymph node size resulted predominantly from a very significant decrease in both the proportions and the total numbers of B220+ DN T cells. The proportions of these cells were reduced up to 20-fold and the total numbers per LN up to 400-fold. Although chronic treatment with anti-CD8 mAb had the most profound effects on B220+ DN T cells, it also decreased the numbers of CD4+ T cells, CD4+B220+ T cells, and B cells in Ipr and gld LN up to fivefold. In contrast to its impact on lymphoproliferative disease, anti-CD8 mAb therapy had no significant effect on B cell hyperactivity. Comparisons of serum Ig and autoantibody levels in CD8+ T cell-depleted and control mAb-treated Ipr and gld mice revealed no changes in the elevated concentrations of serum IgM or total IgG and no significant reduction in the levels of circulating autoantibodies specific for thymocytes or dsDNA. The presence of active germinal centers and accumulations of plasma cells in the LN and spleen of anti-CD8 mAb-treated Ipr and gld mice provided further evidence for sustained B cell activation. These results suggest that in Ipr and gld mice, CD8+ T cells play a crucial role in the accumulation of B220+ DN T cells and also may contribute to the characteristic increase in the numbers of B cells and CD4+ T cells in these mice, but have no significant effect on B cell hyperactivity or autoantibody production.