Obata Y, Taguchi O, Matsudaira Y, Hasegawa H, Hamasima N, Takahashi T
Laboratory of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan.
J Exp Med. 1991 Aug 1;174(2):351-62. doi: 10.1084/jem.174.2.351.
During derivation of transgenic mouse strains with various TL and TL/H-2 chimeric genes, one strain, Tg.Tlaa-3-1, introduced with a TL gene (Tlaa-3), was found to have an abnormal thymic T cell population and to develop a high incidence of T cell lymphomas. To investigate the etiology of the thymic abnormalities and of the lymphomas, the development of lymphoid organs in transgenic mice was studied. The thymus of these mice goes through three unusual successive events: perturbation of thymic development during embryogenesis, disappearance of thymocytes between day 14 and day 21 after birth, and subsequent proliferation of large blast-like cells. These events are associated with the abolishment of T cell receptor (TCR) alpha beta lineage of the T cell differentiation, leading to preponderance of cells belonging to the TCR gamma delta L3T4-Lyt-2- double negative (DN) lineage. Bone marrow transplantation and thymic graft experiments demonstrate that the abnormality resides in the bone marrow stem cells rather than in the thymic environment. The expression of TL antigen in the transgenic mice is greatly increased and TL is expressed in a wide range of T cells, including normally TL- DN cells and L3T4+ Lyt-2- and L3T4-Lyt-2+ single positive cells. These quantitative and qualitative abnormalities in TL expression most likely cause the abnormal T cell differentiation. The gamma delta DN cells migrate into peripheral lymphoid organs and constitute nearly 50% of peripheral T cells. Immune function of the transgenic mice is severely impaired, as T cell function is defective in antibody production to sheep red blood cells, in mixed lymphocyte culture reaction to allogenic spleen cells and also in stimulation with concanavalin A. These results indicate that the gamma delta cells are incapable of participating in these reactions. Molecular and serological analysis of T cell lymphomas reveal that they belong to the gamma delta lineage, suggesting that the gamma delta DN cells in this strain are susceptible to leukemic transformation. Based on cell surface phenotype and TCR expression of the DN thymocytes and T cell lymphomas, a map of the sequential steps involved in the differentiation of gamma delta DN cells is proposed.(ABSTRACT TRUNCATED AT 400 WORDS)
在培育带有各种TL和TL/H-2嵌合基因的转基因小鼠品系过程中，发现一个导入TL基因（Tlaa-3）的品系Tg.Tlaa-3-1胸腺T细胞群体异常，并出现高发性T细胞淋巴瘤。为研究胸腺异常和淋巴瘤的病因，对转基因小鼠淋巴器官的发育进行了研究。这些小鼠的胸腺经历了三个不同寻常的连续事件：胚胎期胸腺发育受到干扰、出生后第14天至第21天胸腺细胞消失，以及随后大的母细胞样细胞增殖。这些事件与T细胞分化过程中T细胞受体（TCR）αβ谱系的缺失有关，导致属于TCRγδ L3T4-Lyt-2-双阴性（DN）谱系的细胞占优势。骨髓移植和胸腺移植实验表明，异常存在于骨髓干细胞而非胸腺环境中。转基因小鼠中TL抗原的表达大幅增加，TL在广泛的T细胞中表达，包括正常情况下TL-DN细胞以及L3T4+ Lyt-2-和L3T4-Lyt-2+单阳性细胞。TL表达的这些数量和质量异常很可能导致T细胞分化异常。γδ DN细胞迁移到外周淋巴器官，占外周T细胞的近50%。转基因小鼠的免疫功能严重受损，因为T细胞功能在针对绵羊红细胞的抗体产生、对同种异体脾细胞的混合淋巴细胞培养反应以及用刀豆球蛋白A刺激时均有缺陷。这些结果表明γδ细胞无法参与这些反应。对T细胞淋巴瘤的分子和血清学分析表明它们属于γδ谱系，提示该品系中的γδ DN细胞易发生白血病转化。基于DN胸腺细胞和T细胞淋巴瘤的细胞表面表型及TCR表达，提出了γδ DN细胞分化所涉及的连续步骤图谱。（摘要截选至400字）
