Yui K, Bhandoola A, Radic M Z, Komori S, Katsumata M, Greene M I
Department of Pathology and Laboratory Medicine, University of Pennsylvania, School of Medicine, Philadelphia 19104-6082.
Eur J Immunol. 1992 Jul;22(7):1693-700. doi: 10.1002/eji.1830220705.
Mice homozygous for the gld (generalized lymphoproliferative disease) mutation developed systemic autoimmune disease and severe lymphadenopathy due to an age-related accumulation in the peripheral lymphoid organs of polyclonal T cells bearing a unique phenotype (CD4-CD8-TCR alpha beta+B220+). These T cells overexpress T cell receptor (TcR) alpha beta chain RNA, proto-oncogenes c-myb and fyn, and proliferate poorly in response to TcR-mediated stimulation. The origin of these T cells is poorly understood. To study the influence of a functionally rearranged TcR beta chain on the T cell developmental abnormality of the gld mutation and autoimmunity, we have backcrossed TcR V beta 8.1-transgenic mice to C3H-gld/gld to homozygosity (transgenic gld mice). In transgenic gld mice, lymphadenopathy was markedly inhibited and the accumulation of CD4-CD8- T cells did not occur, although the remaining T cells overexpressed c-myb and proliferated poorly in response to TcR occupancy. These features indicate that the pattern of proto-oncogene expression and abnormal function persist in phenotypically normal T cells in transgenic gld mice, and that these characteristics can be dissociated from the accumulation of CD4-CD8- T cells. The hypergammaglobulinemia and anti-double-stranded DNA (anti-dsDNA) antibody production was partially improved in transgenic gld mice, supporting the critical role of T cells in abnormal B cell activation described in autoimmunity-prone mice. To investigate further the mechanisms underlying the inhibition of CD4-CD8- T cell accumulation in transgenic gld mice, the fetal ontogeny of T cells in transgenic mice was compared with that of non-transgenic mice. In transgenic thymus, development of TcR alpha beta+ cells was accelerated as detected by earlier expression of CD4, CD8 and TcR in fetal thymus. In contrast, the number of TcR gamma delta+ cells was reduced. We suggest that altered T cell development in transgenic mice directly or indirectly inhibits the accumulation of abnormal T cells in gld mice.
纯合gld（全身性淋巴细胞增生性疾病）突变的小鼠会患上系统性自身免疫疾病，并出现严重的淋巴结病，这是由于外周淋巴器官中出现了与年龄相关的多克隆T细胞积累，这些T细胞具有独特的表型（CD4-CD8-TCRαβ+B220+）。这些T细胞过度表达T细胞受体（TcR）αβ链RNA、原癌基因c-myb和fyn，并且在对TcR介导的刺激作出反应时增殖能力较差。这些T细胞的起源尚不清楚。为了研究功能重排的TcRβ链对gld突变的T细胞发育异常和自身免疫的影响，我们将TcR Vβ8.1转基因小鼠与C3H-gld/gld小鼠回交至纯合状态（转基因gld小鼠）。在转基因gld小鼠中，淋巴结病受到明显抑制，CD4-CD8-T细胞没有积累，尽管其余的T细胞过度表达c-myb，并且在TcR被占据时增殖能力较差。这些特征表明，在转基因gld小鼠表型正常的T细胞中原癌基因的表达模式和异常功能仍然存在，并且这些特征可以与CD4-CD8-T细胞的积累相分离。转基因gld小鼠的高球蛋白血症和抗双链DNA（抗dsDNA）抗体产生得到了部分改善，这支持了T细胞在易患自身免疫疾病小鼠中异常B细胞激活中所起的关键作用。为了进一步研究转基因gld小鼠中CD4-CD8-T细胞积累受到抑制的潜在机制，将转基因小鼠的T细胞胚胎发育过程与非转基因小鼠进行了比较。在转基因胸腺中，通过胎儿胸腺中CD4、CD8和TcR的早期表达检测到，TcRαβ+细胞的发育加速。相反，TcRγδ+细胞的数量减少。我们认为，转基因小鼠中T细胞发育的改变直接或间接抑制了gld小鼠中异常T细胞的积累。
