Kersh G J, Engle D L, Williams C B, Allen P M
Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Immunol. 2000 Jun 1;164(11):5675-82. doi: 10.4049/jimmunol.164.11.5675.
Positive and negative selection of thymocytes is determined by the specificity of the TCR and signaling through its associated molecules. We have studied selection of thymocytes bearing a MHC class II-restricted TCR using fetal thymic organ culture. This system allows the addition of peptides to the already diverse panoply of endogenous peptide ligands and is useful for analyzing ligand-specific negative selection of CD4 single positive (CD4SP) thymocytes. The data reveal that the ability of a given ligand to mediate negative selection is related to its dissociation rate from the TCR. We find that negative selection is very sensitive, and only the weakest ligand that we can identify fails to induce negative selection. None of the numerous peptides tested were able to induce an increase in CD4SP thymocytes. In addition, the ligands that induce negative selection of CD4SP thymocytes also cause an increase in numbers of CD8SP thymocytes bearing high levels of the class II-restricted TCR. Although these cells have a cell surface phenotype consistent with positive selection, they most likely represent cells in the process of negative selection. Further analysis reveals that these cells are not induced by these ligands in intact adult animals and that their induction is probably only revealed in the organ culture system.
胸腺细胞的阳性和阴性选择由TCR的特异性及其相关分子的信号传导决定。我们利用胎胸腺器官培养研究了携带II类MHC限制性TCR的胸腺细胞的选择。该系统允许向内源性肽配体的多样组合中添加肽，并且可用于分析CD4单阳性（CD4SP）胸腺细胞的配体特异性阴性选择。数据显示，给定配体介导阴性选择的能力与其从TCR的解离速率相关。我们发现阴性选择非常敏感，只有我们能鉴定出的最弱配体不能诱导阴性选择。所测试的众多肽中没有一种能够诱导CD4SP胸腺细胞增加。此外，诱导CD4SP胸腺细胞阴性选择的配体也会导致携带高水平II类限制性TCR的CD8SP胸腺细胞数量增加。虽然这些细胞具有与阳性选择一致的细胞表面表型，但它们很可能代表处于阴性选择过程中的细胞。进一步分析表明，这些细胞在完整的成年动物中不会被这些配体诱导，并且它们的诱导可能仅在器官培养系统中显现出来。
