CHARACTERIZATION OF CELL SURFACE MOLECULES IMPORTANT FOR IMMUNE FUNCTION

在之前的体外研究中，我们提出了细胞外基质成分层粘连蛋白-2及其整合素受体VLA-6在胸腺细胞发育中的作用。两个在层粘连蛋白-2中存在不同缺陷的营养不良小鼠品系的特征使我们能够在体内检验这一提议。与正常小鼠相比，层粘连蛋白-2缺陷小鼠的胸腺大小和胸腺细胞数量显著减少。这些小鼠也表现出胸腺结构的明显变化。Dy/dy胸腺中的CD_4/CD_8细胞群检测结果显示，DN(CD_4-CD_8~-)和SP(CD_4~+CD_8~-，CD_4~-CD_8~+)相对较大地增加，而DP(CD_4~+CD_8~+)则显著减少。对糖尿病肾病患者CD44和CD25表达的进一步检测显示，在更成熟的前T细胞人群中，CD44和CD25的表达显著减少。Dy/Dy胸腺的原位和流式细胞术分析显示，包膜和包膜下区域的DN胸腺细胞的凋亡率显著增加。有趣的是，在表达层粘连蛋白-2突变形式dy2J的营养不良小鼠中，胸腺细胞的发育似乎正常进行，在胎儿和新生dy/dy小鼠中也是如此。我们认为层粘连蛋白-2通过在幼年小鼠发育的特定阶段传递细胞存活和分化信号而在胸腺细胞发育中发挥积极作用。

In previous in vitro studies, we proposed a role for the extracellular matrix component, laminin-2, and its integrin receptor, VLA-6 in thymocyte development. The characterization of two dystrophic mouse strains with different defects in laminin-2 allowed us to examine this proposal in vivo. Mice deficient in laminin-2, dy/dy, show a significant reduction in thymus size and number of thymocytes compared to normal littermates. These mice also exhibited apparent alterations of thymic architecture. Examination of the CD4/CD8 populations in dy/dy thymi showed large relative increases in the DN (CD4-CD8-) and SP (CD4+CD8-, CD4-CD8+) populations and a significant decrease in the DP (CD4+CD8+) population. Further examination of the DN population for CD44 and CD25 expression showed a remarkable decrease in the more mature pre-T cell populations. Analysis of apoptosis in situ, and by flow cytometry, in dy/dy thymi revealed a significant increase in apoptotic DN thymocytes in the capsule and subcapsular regions. Interestingly, thymocyte development appeared to proceed normally in dystrophic mice expressing a mutant form of laminin-2, dy2J, as well as, in fetal and neonatal dy/dy mice. We propose that laminin-2 plays an active role in thymocyte development by delivering cell survival and differentiation signals at specific stages of development in young adult mice.