Giese T, Davidson W F
Laboratory of Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Int Immunol. 1995 Aug;7(8):1213-23. doi: 10.1093/intimm/7.8.1213.
Mice homozygous for lpr or gld develop lymphoproliferative disease characterized by the progressive accumulation of functionally impaired B220+ double-negative (DN) T cells and primed CD4+ and CD8+ T cells. The mechanisms leading to the accumulation of these T cells subsets are poorly understood but are clearly dependent on lack of expression of Fas in lpr mice and expression of defective FasL in gld mice. A role for V beta 8+ T cells also has been reported. Recently, a variety of experimental approaches revealed that the majority of B220+ DN T cells are derived from MHC class I-selected CD8+ precursors. Here we used the potent mitogen, staphylococcal enterotoxin B (SEB): (i) to examine the effects of defective Fas-FasL expression on the deletion of peripheral V beta 8+ T cells in 6- to 8- and 20-week old C3H-lpr and -gld mice, (ii) to determine the immunocompetence of B220+ DN T cells in vivo, and (iii) to determine if activated V beta 8+ CD8+ T cells can differentiate into B220+ DN T cells. The role of V beta 8+ T cells in the accumulation of B220+ DN T cells also was reinvestigated. These studies showed that deletion pathways independent of Fas-FasL expression function in young lpr and gld mice and delete CD4+ T cells more efficiently than CD8+ T cells. As the mice age, these alternative pathways become less effective and this may explain the progressive accumulation of memory T cells. No abnormalities in tolerance induction were observed in young or diseased mice. Stimulation of +/+, lpr and gld V beta 8+ CD8+ T cells induced the expression of B220. B220 levels were maximal 2 days after SEB and were undetectable 5 days later, suggesting that B220 is a transiently expressed activation marker on CD8+ T cells. Neither the B220+ V beta 8+ CD8+ T cells nor other V beta 8+ T cell populations converted with detectable frequency into B220+ DN T cells after single or multiple doses of SEB. B220+ DN T cells, which are functionally anergic in vitro, did not proliferate or undergo deletion after SEB stimulation indicating that these cells also are functionally impaired in vivo. In contrast to previous reports, chronic elimination of V beta 8+ T cells had no effect on the accumulation of B220+ DN T cells.(ABSTRACT TRUNCATED AT 400 WORDS)
lpr或gld基因纯合的小鼠会发生淋巴细胞增生性疾病，其特征是功能受损的B220 +双阴性（DN）T细胞以及致敏的CD4 +和CD8 + T细胞逐渐积累。导致这些T细胞亚群积累的机制尚不清楚，但显然取决于lpr小鼠中Fas表达的缺失以及gld小鼠中缺陷型FasL的表达。也有报道称Vβ8 + T细胞发挥了作用。最近，各种实验方法表明，大多数B220 + DN T细胞源自MHC I类选择的CD8 +前体。在这里，我们使用强效促细胞分裂剂葡萄球菌肠毒素B（SEB）：（i）检查缺陷型Fas - FasL表达对6至8周龄和20周龄C3H - lpr和 - gld小鼠外周Vβ8 + T细胞缺失的影响，（ii）确定体内B220 + DN T细胞的免疫活性，以及（iii）确定活化的Vβ8 + CD8 + T细胞是否可以分化为B220 + DN T细胞。还重新研究了Vβ8 + T细胞在B220 + DN T细胞积累中的作用。这些研究表明，在年轻的lpr和gld小鼠中，存在独立于Fas - FasL表达的缺失途径，并且该途径对CD4 + T细胞的删除效率高于CD8 + T细胞。随着小鼠年龄的增长，这些替代途径的效果会变差，这可能解释了记忆T细胞的逐渐积累。在年轻或患病小鼠中未观察到耐受性诱导异常。对+/ +、lpr和gld Vβ8 + CD8 + T细胞的刺激诱导了B220的表达。SEB刺激后2天B220水平最高，5天后无法检测到，这表明B220是CD8 + T细胞上瞬时表达的活化标志物。单次或多次注射SEB后，B220 + Vβ8 + CD8 + T细胞和其他Vβ8 + T细胞群体均未以可检测到的频率转化为B220 + DN T细胞。在体外功能无反应性的B220 + DN T细胞在SEB刺激后不增殖或不发生删除，这表明这些细胞在体内功能也受损。与先前的报道相反，慢性清除Vβ8 + T细胞对B220 + DN T细胞的积累没有影响。（摘要截短至400字）
