THE ACCUMULATION OF B220(+) CD4(-) CD8(-) (DN) T-CELLS IN C3H-LPR/LPR MICE IS NOT ACCELERATED BY THE STIMULATION OF CD8(+) T-CELLS OR B220(+) DN T-CELLS WITH STAPHYLOCOCCAL-ENTEROTOXIN-B AND OCCURS INDEPENDENTLY OF V(BETA)8(+) T-CELLS
THE ACCUMULATION OF B220(+) CD4(-) CD8(-) (DN) T-CELLS IN C3H-LPR/LPR MICE IS NOT ACCELERATED BY THE STIMULATION OF CD8(+) T-CELLS OR B220(+) DN T-CELLS WITH STAPHYLOCOCCAL-ENTEROTOXIN-B AND OCCURS INDEPENDENTLY OF V(BETA)8(+) T-CELLS
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DOI：
10.1093/intimm/7.8.1213
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发表时间：
1995-08-01
影响因子：
4.4
通讯作者：
DAVIDSON, WF
中科院分区：
文献类型：
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作者：
GIESE, T;DAVIDSON, WF
Ipr或gld纯合子小鼠发生淋巴组织增生性疾病，其特征为功能受损的B220（+）双阴性（DN）T细胞和致敏的CD 4（+）和CD 8（+）T细胞的进行性积累。导致这些T细胞亚群积累的机制知之甚少，但显然依赖于Ipr小鼠中Fas表达的缺乏和gld小鼠中Fast缺陷的表达。V（beta）8（+）T细胞的作用也有报道。最近，各种实验方法显示，大多数B220（+）DN T细胞来源于MHC I类选择性CD 8（+）前体。在这里，我们使用了有效的有丝分裂原，葡萄球菌肠毒素8（SEB）：（i）在6-至8-和20周龄C3 H-Ipr和-gld小鼠中检测缺陷性Fas-FasL表达对外周V（β）8（+）T细胞缺失的影响，（ii）测定体内B220（+）DN T细胞的免疫活性，和（iii）确定活化的V（β）8（+）CD 8（+）T细胞是否可以分化成B220（+）DN T细胞。还重新研究了V（beta）8（+）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Ipr和gld小鼠中，不依赖于Fas-FasL表达的缺失途径发挥作用，并且比CD 8（+）T细胞更有效地缺失CD 4（+）T细胞。随着小鼠年龄的增长，这些替代途径变得不那么有效，这可以解释记忆T细胞的渐进积累。在年幼或患病小鼠中未观察到耐受性诱导异常。刺激+/+、Ipr和gld V（beta）8（+）CD 8（+）T细胞可诱导B220的表达，B220水平在SEE后2天达到最高，5天后检测不到，提示B220是CD 8（+）T细胞上瞬时表达的活化标志物。在单次或多次剂量的SEB后，B220（+）V（beta）8（+）CD 8（+）T细胞和其他V（beta）8（+）T细胞群均未以可检测的频率转化为B220（+）DN T细胞。B220（+）DN T细胞在体外是功能性无能的，在SEB刺激后不增殖或经历缺失，表明这些细胞在体内也是功能性受损的。与以前的报道相反，V（β）8（+）T细胞的慢性消除对B220（+）DN T细胞的积累没有影响。这些数据表明，首先，B220（+）DN T细胞的积累不太可能仅仅通过抗原诱导的B220（+）DN T细胞增殖而发生，而且可能依赖于推定的CD 8（+）MHC I类选择的前体向B220（+）DN T细胞的连续转化。其次，在外周中避免缺失的强活化的CD 8（+）T细胞不太可能是B220（+）DN T细胞的来源。
Mice homozygous for Ipr 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 cell subsets are poorly understood but are clearly dependent on lack of expression of Fas in Ipr mice and expression of defective Fast 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 8 (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-Ipr 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 Ipr 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 +/+, Ipr and gld V(beta)8(+) CD8(+) T cells induced the expression of B220, B220 levels were maximal 2 days after SEE 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. These data suggest, first, that the accumulation of B220(+) DN T cells is unlikely to occur solely by antigen-induced proliferation of B220(+) DN T cells but also may be dependent on the continuous conversion of putative CD8(+) MHC class I selected precursors into B220(+) DN T cells. Second, strongly activated CD8(+) T cells that avoid deletion in the periphery are an unlikely source of B220(+) DN T cells.