Giese T, Davidson W F
Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1992 Nov 1;149(9):3097-106.
Mice homozygous for lpr and gld develop profound lymphadenopathy characterized by the accumulation of two functionally anergic T cell subsets, a predominant B220+CD4-CD8- double negative (DN) population and a minor, closely related CD4 dull+ B220+ population. Lymph nodes from diseased lpr and gld mice also contain abnormally high numbers of conventional T cells, and we reported recently that a high proportion of lpr and gld CD4+B220- T cells have the hallmarks of primed or memory T cells. In the present study, we further investigated the extent, ontogeny, and possible causes of T cell activation in lpr and gld mice. The criteria used to identify primed or memory T cells included activation-dependent increases in the expression of CD44, LFA-1, and the early activation Ag, CD69, and decreases in the expression of Mel-14 and CD45RB, as well as quantitative differences in the in vitro production of IFN-gamma and the TNF-alpha by stimulated cells. A comparison of TCR V beta gene utilization by lpr T cell subsets also was undertaken. The results showed that T cell activation was widespread and complex. CD8+ T cells exhibited a similar pattern of activation to CD4+B220- T cells. The activation of these two subsets occurred in parallel, was in evidence by 4 to 6 wk of age, and was both chronic and progressive. The proportions of CD44hiLFA-1hi, CD4+B220-, and CD8+ T cells increased steadily between 4 and 20 wk of age, but changes in T cell growth, Mel-14, and CD45RB expression and cytokine secretion were not observed until mice were older than 11 wk. A very different pattern of activation was observed for B220+ T cells. At all ages, B220+ DN and CD4+B220+ T cells were CD44hiMel-14hi and 60 to 75% were CD69+. The expression of CD69 appeared to be stimulus dependent rather than constitutive, suggesting that these cells, too, may be chronically stimulated in vivo. In keeping with their anergic state, DN T cells responded poorly to cross-linking of CD69. The stimuli inducing chronic activation of CD4+B220- and CD8+ T cells are unlikely to include inappropriate reactions to autoantigens because there was no evidence for selective accumulation of CD4+ or CD8+ T cells bearing particular V beta genes or potentially self-reactive cells that normally are deleted in the thymus. By comparison, C3H-lpr DN cells displayed some potentially significant differences in V beta 6 and V beta 9 expression from CD4+B220- and CD8+ T cells.(ABSTRACT TRUNCATED AT 400 WORDS)
纯合 lpr 和 gld 的小鼠会出现严重的淋巴结病，其特征是两个功能无反应性的 T 细胞亚群积累，一个主要是 B220 + CD4 - CD8 - 双阴性（DN）群体，另一个是少量的、密切相关的 CD4 低表达 + B220 + 群体。患病的 lpr 和 gld 小鼠的淋巴结中还含有异常高数量的常规 T 细胞，并且我们最近报道，lpr 和 gld 的 CD4 + B220 - T 细胞中有很大比例具有已致敏或记忆 T 细胞的特征。在本研究中，我们进一步研究了 lpr 和 gld 小鼠中 T 细胞活化的程度、发生过程及可能原因。用于鉴定已致敏或记忆 T 细胞的标准包括 CD44、LFA - 1 和早期活化抗原 CD69 表达的活化依赖性增加，以及 Mel - 14 和 CD45RB 表达的降低，还有刺激细胞体外产生 IFN - γ 和 TNF - α 的定量差异。我们还对 lpr T 细胞亚群的 TCR Vβ 基因利用情况进行了比较。结果表明，T 细胞活化广泛且复杂。CD8 + T 细胞表现出与 CD4 + B220 - T 细胞相似的活化模式。这两个亚群的活化同时发生，在 4 至 6 周龄时明显，且是慢性和进行性的。在 4 至 20 周龄之间，CD44hiLFA - 1hi 的 CD4 + B220 - 和 CD8 + T 细胞比例稳步增加，但直到小鼠超过 11 周龄才观察到 T 细胞生长、Mel - 14 和 CD45RB 表达以及细胞因子分泌的变化。对于 B220 + T 细胞，观察到一种非常不同的活化模式。在所有年龄段，B220 + DN 和 CD4 + B220 + T 细胞都是 CD44hiMel - 14hi，60%至 75%是 CD69 +。CD69 的表达似乎依赖于刺激而非组成性表达，这表明这些细胞在体内也可能受到慢性刺激。与它们的无反应状态一致，DN T 细胞对 CD69 的交联反应不佳。诱导 CD4 + B220 - 和 CD8 + T 细胞慢性活化的刺激不太可能包括对自身抗原的不适当反应，因为没有证据表明携带特定 Vβ 基因的 CD4 + 或 CD8 + T 细胞或通常在胸腺中被清除的潜在自身反应性细胞有选择性积累。相比之下，C3H - lpr DN 细胞在 Vβ6 和 Vβ9 表达上与 CD4 + B220 - 和 CD8 + T 细胞显示出一些潜在的显著差异。（摘要截短至 400 字）
