Zhou T, Bluethmann H, Zhang J, Edwards C K, Mountz J D
Department of Medicine, University of Alabama, Birmingham 35294.
J Exp Med. 1992 Oct 1;176(4):1063-72. doi: 10.1084/jem.176.4.1063.
In normal mice neonatal injection of staphylococcal enterotoxin B (SEB) induces tolerance in T cells that express reactive T cell receptor (TCR) V beta regions. To determine if a T cell neonatal defect was present in MRL-lpr/lpr mice, 20 micrograms of SEB was injected intraperitoneally every other day into V beta 8.2 TCR transgenic and nontransgenic MRL(-)+/+ and MRL-lpr/lpr mice from birth to 2 wk of age. At 2 wk of age, V beta 8+ T cells were depleted, and SEB reactivity was lost, in spleen, lymph node, and thymus. These effects were equivalent in +/+ and lpr/lpr SEB-tolerized mice. However, MRL-lpr/lpr mice failed to maintain neonatal tolerance. By 4 wk of age, there was a dramatic increase in T cells expressing V beta 8.2 in the peripheral lymph nodes of MRL-lpr/lpr mice but not MRL(-)+/+ mice. In vitro stimulation with SEB or TCR crosslinking revealed a total loss of neonatal tolerance 2 wk after cessation of SEB treatment in lpr/lpr mice, but not +/+ mice. The time-course of recovery of V beta 8+ T cells and reactivity to SEB and TCR crosslinking in the thymus of MRL-lpr/lpr mice was similar to that in the lymph node. Thymectomy at 2 wk of age eliminated tolerance loss in lymph nodes of MRL-lpr/lpr mice at 4 wk of age, indicating that loss of peripheral tolerance was due to the emigration of untolerized T cells from the thymus. Challenge of neonatally tolerized MRL-lpr/lpr mice with SEB (100 micrograms, i.p.) at 8 wk of age resulted in a dramatic onset of T cell-mediated autoimmune disease characterized by 30% weight loss and 60% morality. This indicated that loss of tolerance to SEB also occurred in vivo. In contrast, neonatally tolerized MRL(-)+/+ mice remained totally unresponsive to SEB challenge and did not undergo any detectable weight loss. These results suggest that there is normal induction of neonatal tolerance to SEB in lpr/lpr mice, but that tolerance is not maintained after the tolerizing antigen is removed. This loss of neonatal tolerance can lead to severe weight loss and death on exposure to the tolerizing antigen later in life.
在正常小鼠中，新生期注射葡萄球菌肠毒素B（SEB）可诱导表达反应性T细胞受体（TCR）Vβ区域的T细胞产生耐受性。为了确定MRL-lpr/lpr小鼠是否存在T细胞新生期缺陷，从出生至2周龄，每隔一天给Vβ8.2 TCR转基因和非转基因的MRL(-)+/+及MRL-lpr/lpr小鼠腹腔注射20微克SEB。在2周龄时，脾脏、淋巴结和胸腺中的Vβ8 + T细胞减少，且SEB反应性丧失。在 +/+和lpr/lpr SEB耐受小鼠中，这些效应是相同的。然而，MRL-lpr/lpr小鼠未能维持新生期耐受性。到4周龄时，MRL-lpr/lpr小鼠外周淋巴结中表达Vβ8.2的T细胞显著增加，而MRL(-)+/+小鼠则没有。用SEB或TCR交联进行体外刺激显示，在lpr/lpr小鼠中，停止SEB治疗后2周，新生期耐受性完全丧失，而 +/+小鼠则没有。MRL-lpr/lpr小鼠胸腺中Vβ8 + T细胞的恢复时间进程以及对SEB和TCR交联的反应性与淋巴结中的相似。2周龄时进行胸腺切除消除了4周龄时MRL-lpr/lpr小鼠淋巴结中的耐受性丧失，表明外周耐受性的丧失是由于未耐受的T细胞从胸腺中迁出。8周龄时，用SEB（100微克，腹腔注射）对新生期耐受的MRL-lpr/lpr小鼠进行攻击，导致T细胞介导的自身免疫性疾病急剧发作，其特征为体重减轻30%和死亡率60%。这表明在体内也发生了对SEB耐受性丧失。相比之下，新生期耐受的MRL(-)+/+小鼠对SEB攻击仍完全无反应，且未出现任何可检测到的体重减轻。这些结果表明，lpr/lpr小鼠对SEB的新生期耐受性诱导正常，但在去除耐受抗原后耐受性无法维持。这种新生期耐受性的丧失可导致在生命后期接触耐受抗原时出现严重体重减轻和死亡。
