Dulude G, Brochu S, Fontaine P, Baron C, Gyger M, Roy D C, Perreault C
Department of Medicine, University of Montreal, and Research Center, Maisonneuve-Rosemont Hospital, Quebec, Canada.
Exp Hematol. 1997 Aug;25(9):992-1004.
Thymic function is severely impaired in most marrow transplant recipients. To evaluate the impact of thymic hypoplasia on T cell reconstitution following marrow transplantation, we compared the phenotype and function of T lymphocytes in thymectomized recipients with those of euthymic hosts. Irradiated C57BL/6 mice (Thy1.2+, Ly5.1+) received 10(7) T cell-depleted B6.Ly5.2 bone marrow cells (Thy1.2+, Ly5.2+), with or without 3 x 10(5) B6.PL lymph node cells (Thy1.1+, Ly5.1+) as a source of T lymphocytes. Multiparameter flow cytometry analysis showed that in euthymic mice (group 1), T cell reconstitution was carried out by donor hematopoietic stem cells that differentiated in the host's thymus, whereas the production of chimeric T cells in athymic recipients depended on the presence or absence of T cells in the graft. When T lymphocytes were present in the graft (group 2), their progeny constituted the vast majority of splenic T cells on day 100 posttransplant. When the graft did not contain T lymphocytes (group 3), T cell reconstitution resulted from extrathymic maturation of donor hematopoietic progenitors; T cells differentiating along this pathway expressed lower levels of T cell receptor and a large proportion of the CD8+ subset expressed CD8alpha alpha homodimers. The T cell receptor Vbeta profile of all chimeras was similar to that of normal C57BL/6 mice. Compared with T cells found in euthymic recipients, those in mice from groups 2 and 3 were less abundant (particularly with respect to the CD4+ subset), displayed the CD44/CD45 phenotype of activated memory cells, and expressed high levels of IL-2 receptor beta chain. These results show that both the presence or absence of the thymus and the composition of the grafted inoculum determine the source and extent of posttransplant T cell reconstitution. Because they determine the nature of the differentiation pathway taken during T cell development in the host, these two factors can exert a critical influence on the appearance of graft vs. host disease and the level of host immunocompetence.
大多数骨髓移植受者的胸腺功能严重受损。为了评估胸腺发育不全对骨髓移植后T细胞重建的影响，我们比较了胸腺切除受者与正常胸腺宿主的T淋巴细胞表型和功能。对受照射的C57BL/6小鼠（Thy1.2 +，Ly5.1 +）输注10^7个去除T细胞的B6.Ly5.2骨髓细胞（Thy1.2 +，Ly5.2 +），同时或不同时输注3×10^5个B6.PL淋巴结细胞（Thy1.1 +，Ly5.1 +）作为T淋巴细胞来源。多参数流式细胞术分析显示，在有正常胸腺的小鼠（第1组）中，T细胞重建是由在宿主胸腺中分化的供体造血干细胞完成的，而无胸腺受者中嵌合T细胞的产生取决于移植物中是否存在T细胞。当移植物中存在T淋巴细胞时（第2组），其后代在移植后100天构成脾脏T细胞的绝大多数。当移植物中不含有T淋巴细胞时（第3组），T细胞重建是由供体造血祖细胞的胸腺外成熟导致的；沿此途径分化的T细胞表达较低水平的T细胞受体，并且很大比例的CD8 +亚群表达CD8αα同型二聚体。所有嵌合体的T细胞受体Vβ谱与正常C57BL/6小鼠相似。与有正常胸腺受者中的T细胞相比，第2组和第3组小鼠中的T细胞数量较少（特别是CD4 +亚群），表现出活化记忆细胞的CD44/CD45表型，并表达高水平的IL-2受体β链。这些结果表明，胸腺的有无以及移植接种物的组成都决定了移植后T细胞重建的来源和程度。由于它们决定了宿主中T细胞发育过程中所采用的分化途径的性质，这两个因素可对移植物抗宿主病的出现和宿主免疫能力水平产生关键影响。
