Mixter P F, Russell J Q, Durie F H, Budd R C
Department of Medicine, University of Vermont College of Medicine, Burlington 05405.
J Immunol. 1995 Mar 1;154(5):2063-74.
The CD4-CD8- T cells that accumulate in lpr/lpr mice have previously expressed CD8, on the basis of studies of CD8 alpha gene demethylation. The actual requirement for CD8 interaction with class I MHC molecules to promote the appearance of CD4-CD8- T cells in lpr/lpr mice has also been suggested. To examine this point in more detail, the lpr mutation was bred onto a beta 2-microglobulin-deficient background (beta 2-m-/-). C57BL/6 (B6) mice homozygous for both the lpr mutation of the fas gene and inactivation of the beta 2-m gene (beta 2-m-/- lpr/lpr) develop less alpha beta T cell lymphadenopathy than the parental B6 lpr/lpr strain. This is caused by the near absence of CD8+ T cells and a considerable reduction in CD4-CD8- T cells, revealing an important role for positive selection on class I MHC molecules during the ontogeny of lpr CD4-CD8- T cells. Although absolute numbers of peripheral T cells are decreased in beta 2-m-/- lpr/lpr mice, they manifest a B cell lymphadenopathy with age. beta 2-m-/- lpr/lpr mice display only subtle indications of autoimmune disease with age, compared with parental B6 (beta 2-m+/+)lpr/lpr mice. These include limited histopathologic stages of kidney disease and lack of proteinuria, despite the presence of serum anti-DNA Abs. Thus, absence of class I MHC-positive selection of CD8+ and CD4-CD8- TCR-alpha beta + cells limits the autoimmune diathesis observed in beta 2-m+/+ lpr/lpr mice.
基于对CD8α基因去甲基化的研究，在lpr/lpr小鼠中积累的CD4-CD8-T细胞先前已表达CD8。也有人提出，在lpr/lpr小鼠中，CD8与I类MHC分子相互作用对于促进CD4-CD8-T细胞的出现具有实际需求。为了更详细地研究这一点，将lpr突变培育到β2-微球蛋白缺陷背景（β2-m-/-）上。fas基因的lpr突变和β2-m基因失活（β2-m-/- lpr/lpr）均纯合的C57BL/6（B6）小鼠，其αβT细胞淋巴结病的发展程度低于亲本B6 lpr/lpr品系。这是由于几乎没有CD8+ T细胞以及CD4-CD8-T细胞大量减少所致，这揭示了在lpr CD4-CD8-T细胞个体发育过程中，I类MHC分子阳性选择的重要作用。尽管β2-m-/- lpr/lpr小鼠外周T细胞的绝对数量减少，但它们随着年龄增长会出现B细胞淋巴结病。与亲本B6（β2-m+/+)lpr/lpr小鼠相比，β2-m-/- lpr/lpr小鼠随着年龄增长仅表现出轻微的自身免疫疾病迹象。这些迹象包括肾病的组织病理学阶段有限且无蛋白尿，尽管存在血清抗DNA抗体。因此，缺乏I类MHC对CD8+和CD4-CD8-TCR-αβ+细胞的阳性选择，限制了在β2-m+/+ lpr/lpr小鼠中观察到的自身免疫素质。
