Wang B, She J, Salio M, Allen D, Lacy E, Lonberg N, Terhorst C
Beth Israel Deaconess Medical Center, Division of Immunology, Boston, MA 02215, USA.
Mol Med. 1997 Jan;3(1):72-81.
Upon engagement of the T cell receptor for antigen, its associated CD3 proteins recruit signal transduction molecules, which in turn regulate T lymphocyte proliferation, apoptosis, and thymocyte development. Because some signal transducing molecules recruited by CD3-epsilon, i.e., p56lck and p59fyn, are oncogenic and since we previously found that overexpression of CD3-epsilon transgenes causes a block in T lymphocyte and NK cell development, we tested the hypothesis that aberrant CD3-epsilon signaling leads both to abnormal T lymphocyte death and lymphomagenesis.
Ten independently derived transgenic mouse lines were generated with four different genomic CD3-epsilon constructs. Mice either homozygous or hemizygous for each transgene were analyzed for an arrest in T lymphocyte development and for the occurrence of T cell lymphomas.
Aggressive clonal T cell lymphomas developed at very high frequencies in seven mouse lines with intermediate levels of copies of CD3-epsilon derived transgenes. However, these lymphomas were not found when high copy numbers of CD3-epsilon transgenes caused a complete block in early thymic development or when a transgene was used in which the exons coding for the CD3-epsilon protein were deleted. Analyses of a series of double mutant mice, tgCD3-epsilon x RAG-2null, indicated that lymphomagenesis was initiated in lineage-committed prothymocytes, i.e., before rearrangement of the T cell receptor genes. In addition, the transgene coding for the CD3-epsilon cytoplasmic domain and its transmembrane region induced a T cell differentiation signal in premalignant tgCD3-epsilon x RAG-2null mice.
The nonenzymatic CD3-epsilon protein acted as a potent oncogene when overexpressed early in T lymphocyte development. Lymphomagenesis was dependent on signal transduction events initiated by the cytoplasmic domain of CD3-epsilon.
当T细胞抗原受体被激活时，与其相关的CD3蛋白会募集信号转导分子，进而调节T淋巴细胞的增殖、凋亡以及胸腺细胞的发育。由于CD3-ε募集的一些信号转导分子，即p56lck和p59fyn，具有致癌性，且我们之前发现CD3-ε转基因的过表达会导致T淋巴细胞和自然杀伤细胞发育受阻，因此我们检验了异常的CD3-ε信号传导会导致T淋巴细胞异常死亡和淋巴瘤发生的假说。
用四种不同的基因组CD3-ε构建体产生了十个独立衍生的转基因小鼠品系。对每个转基因的纯合或半合子小鼠进行分析，以检测T淋巴细胞发育停滞情况以及T细胞淋巴瘤的发生情况。
在七个携带中等拷贝数CD3-ε衍生转基因的小鼠品系中，侵袭性克隆性T细胞淋巴瘤以非常高的频率发生。然而，当高拷贝数的CD3-ε转基因导致早期胸腺发育完全受阻时，或者当使用缺失编码CD3-ε蛋白外显子的转基因时，未发现这些淋巴瘤。对一系列双突变小鼠tgCD3-ε×RAG-2基因敲除小鼠的分析表明，淋巴瘤发生起始于定向祖胸腺细胞，即在T细胞受体基因重排之前。此外，编码CD3-ε胞质结构域及其跨膜区域的转基因在癌前tgCD3-ε×RAG-2基因敲除小鼠中诱导了T细胞分化信号。
非酶促的CD3-ε蛋白在T淋巴细胞发育早期过表达时可作为一种强效癌基因。淋巴瘤的发生依赖于由CD3-ε胞质结构域引发的信号转导事件。
