van Meerwijk J P, Marguerat S, MacDonald H R
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
J Immunol. 1998 Mar 15;160(6):2730-4.
The involvement of a variety of clonal selection processes during the development of T lymphocytes in the thymus has been well established. Less information, however, is available on how homeostatic mechanisms may regulate the generation and maturation of thymocytes. To investigate this question, mixed radiation bone marrow chimeras were established in which wild-type T cell precursors capable of full maturation were diluted with precursors deficient in maturation potential because of targeted mutations of the RAG1 or TCR-alpha genes. In chimeras in which the majority of thymocytes are blocked at the CD4- CD8- CD25+ stage (RAG1 deficient), and only a small proportion of T cell precursors are of wild-type origin, we observed no difference in the maturation of wild-type CD4- CD8- CD25+ cells to the CD4+ CD8+ stage as compared with control chimeras. Therefore, the number of cell divisions occurring during this transition is fixed and not subject to homeostatic regulation. In contrast, in mixed chimeras in which the majority of thymocytes are blocked at the CD4+ CD8+ stage (TCR-alpha deficient), an increased efficiency of development of wild-type mature CD8+ cells was observed. Surprisingly, the rate of generation of mature CD4+ thymocytes was not affected in these chimeras. Thus, the number of selectable CD8 lineage thymocytes apparently saturates the selection mechanism in normal mice while the development of CD4 lineage cells seems to be limited only by the expression of a suitable TCR. These data may open the way to the identification of homeostatic mechanisms regulating thymic output and CD4/CD8 lineage commitment, and the development of means to modulate it.
胸腺中T淋巴细胞发育过程中多种克隆选择过程的参与已得到充分证实。然而，关于稳态机制如何调节胸腺细胞的产生和成熟的信息较少。为了研究这个问题，建立了混合辐射骨髓嵌合体，其中能够完全成熟的野生型T细胞前体与由于RAG1或TCR-α基因的靶向突变而缺乏成熟潜力的前体进行了稀释。在大多数胸腺细胞在CD4-CD8-CD25+阶段受阻（RAG1缺陷）且只有一小部分T细胞前体来自野生型的嵌合体中，我们观察到与对照嵌合体相比，野生型CD4-CD8-CD25+细胞向CD4+CD8+阶段的成熟没有差异。因此，在此转变过程中发生的细胞分裂数量是固定的，不受稳态调节。相比之下，在大多数胸腺细胞在CD4+CD8+阶段受阻（TCR-α缺陷）的混合嵌合体中，观察到野生型成熟CD8+细胞的发育效率增加。令人惊讶的是，这些嵌合体中成熟CD4+胸腺细胞的产生速率没有受到影响。因此，正常小鼠中可选择的CD8谱系胸腺细胞数量显然使选择机制饱和，而CD4谱系细胞的发育似乎仅受合适TCR表达的限制。这些数据可能为鉴定调节胸腺输出和CD4/CD8谱系定向的稳态机制以及开发调节它的方法开辟道路。
