Clarification of the role of cells constructing the thymic microenvironment in the early T cell development

我们首先研究了粘附分子在T细胞发育中的作用。将各种单克隆抗体（mAb）添加到小鼠胎儿胸腺（FT）器官培养中，通过将这些细胞与脱氧鸟苷处理的FT叶共培养，诱导来自FT或胎儿肝脏（FL）祖细胞的T细胞发育。我们发现抗pgp -1、抗lfa -1和抗vla -4单抗严重抑制FL祖细胞的早期T细胞发育，但不抑制ft祖细胞。这些发现强烈表明，通过Pgp-1、LFA-1和VLA-4与胸腺微环境中的元素相互作用对于胸腺前祖细胞发育为T细胞是必不可少的。接下来，我们研究了转录因子在早期胸腺T细胞发育中的作用。我们发现TCF-1和GATA-3蛋白的合成同时开始于一小部分最不成熟的FT细胞群，这些细胞的表型为CD4^- cd8 ^- cd44 ^+CD25^-。研究还发现，在FT器官培养系统中，来自FL和FT祖细胞的T细胞发育受到TCF-1或GATA-3反义寡核苷酸的严重抑制。这些结果强烈表明TCF-1和GATA-3在胸腺T细胞发育的早期阶段起着至关重要的作用。

We first investigated the role of adhesion molecules in T cell development. Various monoclonal antibodies (mAb) was added into the murine fetal thymus (FT) organ cultures, where T cell development from FT or fetal liver (FL) progenitors was induced by coculturing these cells with a deoxyguanosine-treated FT lobe. We found that anti-Pgp-1, anti-LFA-1 and anti-VLA-4 mAb severely inhibited the early phase of T cell development from FL but not FT.progenitors. These findings strongly suggest that interactions with elements in the thymic microenvironment through Pgp-1, LFA-1, and VLA-4 are indispensable for prethymic progenitors to develop into T cells.We next investigated the role of transcription factors in the early thymic T cell development. We found that the synthesis of TCF-1 and GATA-3 proteins begins simultaneously in a fraction of the most immature population of FT cells, which have the phenotype of CD4^-CD8^-CD44^+CD25^-. It is also found that the T cell development from FL but FT progenitors in the FT organ culture system is severely inhibited by the addition of antisense oligonucleotides for either TCF-1 or GATA-3. These results strongly suggest that TCF-1 and GATA-3 play an essential role in the initiation of the earliest steps of T cell development in the thymus.