Giese T, Davidson W F
Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1994 Feb 15;152(4):2000-10.
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.
纯合子lpr或gld小鼠会发生自身免疫和进行性淋巴细胞增生性疾病，其特征是功能受损的B220⁺、TCR-α/β⁺、CD4⁻、CD8⁻双阴性（DN）T细胞异常群体的积累。尽管这些细胞来源于胸腺，且似乎已经经历了胸腺阴性选择，但其直接前体的身份以及导致其积累的机制仍知之甚少。在这里，我们研究了CD8⁺T细胞在淋巴细胞增生性疾病发展和自身抗体产生中的作用。我们发现，从3周龄开始至15周龄，用抗CD8单克隆抗体治疗C3H-Ipr或C3H-gld小鼠，可使淋巴结病显著减轻。淋巴结大小的变化主要是由于B220⁺DN T细胞的比例和总数均显著下降。这些细胞比例最多降低20倍，每个淋巴结中的总数最多降低400倍。尽管长期用抗CD8单克隆抗体治疗对B220⁺DN T细胞影响最为显著，但它也使Ipr和gld淋巴结中CD4⁺T细胞、CD4⁺B220⁺T细胞和B细胞的数量最多减少五倍。与对淋巴细胞增生性疾病的影响相反，抗CD8单克隆抗体治疗对B细胞的高活性没有显著影响。对CD8⁺T细胞耗竭的和用对照单克隆抗体治疗的Ipr和gld小鼠的血清免疫球蛋白和自身抗体水平进行比较，结果显示血清IgM或总IgG的升高浓度没有变化，针对胸腺细胞或双链DNA的循环自身抗体水平也没有显著降低。在用抗CD8单克隆抗体治疗过的Ipr和gld小鼠的淋巴结和脾脏中存在活跃的生发中心和浆细胞聚集，这为B细胞的持续活化提供了进一步的证据。这些结果表明，在Ipr和gld小鼠中，CD8⁺T细胞在B220⁺DN T细胞的积累中起关键作用，也可能促成这些小鼠中B细胞和CD4⁺T细胞数量的特征性增加，但对B细胞的高活性或自身抗体产生没有显著影响。
