Mountz J D, Zhou T, Eldridge J, Berry K, Blüthmann H
University of Alabama, Department of Medicine, Birmingham 35294.
J Exp Med. 1990 Dec 1;172(6):1805-17. doi: 10.1084/jem.172.6.1805.
The lpr gene in homozygous form induces development of CD4-CD8-B220+ T cells and lymphadenopathy in MRL and C57BL/6 mice. Although the propensity for excessive production of T cells is related to an intrinsic T cell defect, a thymus is also required because neonatal thymectomy eliminates lymphadenopathy. Recent evidence suggests that excessive production and release of autoreactive T cells from the thymus of lpr/lpr mice might lead to downregulation of CD4 and CD8 as a "fail safe" tolerance mechanism that occurs during late thymic or post-thymic development. To test this hypothesis, T cell receptor (TCR) transgenic mice that produce large numbers of immature thymocytes recognizing the H-2Db and male H-Y antigens were backcrossed with C57BL/6-lpr/lpr mice and MRL-lpr/lpr mice. It was predicted that Db male lpr/lpr mice would produce large numbers of autoreactive T cells during early thymic development that would lead to an accelerated lymphoproliferative disease. In contrast, Db female lpr/lpr mice would produce large numbers of Db H-Y-reactive T cells, but might not develop lymphadenopathy because the male H-Y antigen would not be present. Unexpectedly, there was complete elimination of lymphadenopathy in both male and female TCR transgenic lpr/lpr mice. The elimination of lymphadenopathy was not due to a failure of thymic maturation since the thymus of H-2Db female lpr/lpr mice contained nearly normal numbers of mature thymocytes. Elimination of lymphadenopathy was also not due to a lack of autoreactive T cells in the peripheral lymph nodes (LN) since there was an increased syngeneic mixed lymphocyte proliferative response of LNT cells from transgenic lpr/lpr compared with +/+ mice in vitro. Hypergammaglobulinemia and autoantibody production in the transgenic lpr/lpr was present at levels comparable with or higher than control nontransgenic lpr/lpr mice, suggesting a dissociation of autoantibody production from the lymphoproliferative disease in the TCR transgenic mice. Conversely, the development of lymphadenopathy and production of CD4-CD8-B220+ T cells appear to be intimately linked, as both were completely eliminated in T cells expressing the transgenic TCR. We propose that lymphoproliferation and production of CD4-CD8-6B2+ T cells in lpr/lpr mice is related to decreased expression of the TCR, and providing the T cells with a rearranged TCR transgene overcomes this defect.
纯合形式的lpr基因可诱导MRL和C57BL/6小鼠出现CD4 - CD8 - B220 + T细胞发育及淋巴结病。尽管T细胞过度产生的倾向与内在的T细胞缺陷有关，但胸腺也是必需的，因为新生期胸腺切除可消除淋巴结病。最近的证据表明，lpr/lpr小鼠胸腺中自身反应性T细胞的过度产生和释放可能导致CD4和CD8下调，这是一种在胸腺晚期或胸腺后发育过程中出现的“故障安全”耐受机制。为了验证这一假设，将产生大量识别H - 2Db和雄性H - Y抗原的未成熟胸腺细胞的T细胞受体（TCR）转基因小鼠与C57BL/6 - lpr/lpr小鼠和MRL - lpr/lpr小鼠进行回交。预计Db雄性lpr/lpr小鼠在胸腺早期发育过程中会产生大量自身反应性T细胞，从而导致加速的淋巴细胞增殖性疾病。相反，Db雌性lpr/lpr小鼠会产生大量Db H - Y反应性T细胞，但可能不会发生淋巴结病，因为不存在雄性H - Y抗原。出乎意料的是，雄性和雌性TCR转基因lpr/lpr小鼠的淋巴结病均完全消除。淋巴结病的消除并非由于胸腺成熟失败，因为H - 2Db雌性lpr/lpr小鼠的胸腺中成熟胸腺细胞数量接近正常。淋巴结病的消除也不是由于外周淋巴结（LN）中缺乏自身反应性T细胞，因为与 +/+ 小鼠相比，转基因lpr/lpr小鼠的LN T细胞在体外的同基因混合淋巴细胞增殖反应增强。转基因lpr/lpr小鼠中的高球蛋白血症和自身抗体产生水平与对照非转基因lpr/lpr小鼠相当或更高，这表明在TCR转基因小鼠中自身抗体产生与淋巴细胞增殖性疾病相互分离。相反，淋巴结病的发展和CD4 - CD8 - B220 + T细胞的产生似乎密切相关，因为在表达转基因TCR的T细胞中两者均被完全消除。我们提出，lpr/lpr小鼠中的淋巴细胞增殖和CD4 - CD8 - 6B2 + T细胞的产生与TCR表达降低有关，为T细胞提供重排的TCR转基因可克服这一缺陷。
