Specific requirement for CD3ε in T cell development
Specific requirement for CD3ε in T cell development
复制标题
DOI：
10.1073/pnas.95.25.14909
复制
发表时间：
1998-12-08
影响因子：
11.1
通讯作者：
Love, PE
中科院分区：
文献类型：
--
作者：
DeJarnette, JB;Sommers, CL;Love, PE
T细胞抗原受体（TCR）和前TCR复合物由克隆型异源二聚体与信号转导不变亚基（CD3 γ, -delta， -epsilon和zeta）二聚体组成。通过在小鼠中产生基因特异性突变，研究了单个不变亚基在T细胞发育中的作用。CD3 γ， - δ或zeta突变导致发育不完全阻断，其特征是成熟T细胞数量减少，表达低水平的TCR。相比之下，CD3 epsilon（-/-）小鼠缺乏成熟的T细胞，胸腺细胞发育在早期CD4(-)CD8（-）阶段被阻止。尽管这些结果表明CD3 epsilon对TCR前和TCR表达/功能至关重要，但CD3 γ和CD3 δ基因在CD3 epsilon（-/-）小鼠中的表达也减少，这一事实使其解释变得复杂。因此，尚不清楚CD3 -epsilon（-/-）小鼠的表型是否反映了CD3 γ、- δ和-epsilon缺乏症的集体效应。通过Cre/ loxp介导的重组，从靶向CD3 epsilon基因上去除可选择标记（PGH-NEO），我们产生了缺乏CD3 epsilon但保持密切相关的CD3 γ和CD3 δ基因正常表达的小鼠。这些（CD3 epsilon(Delta/Delta)）小鼠表现出T细胞发育的早期停滞，类似于CD3 epsilon（-/-）小鼠。此外，发育缺陷可以通过表达CD3 epsilon转基因来修复。这些结果确定了CD3E在T细胞发育中的重要作用，而CD3 γ， CD3 δ或ζ家族蛋白并不共享，并提供了PGK-NEO可以影响其邻近基因表达的进一步证据。
T cell antigen receptor (TCR) and pre-TCR complexes are composed of clonotypic heterodimers in association with dimers of signal transducing invariant subunits (CD3 gamma, -delta, -epsilon, and zeta). The role of individual invariant subunits in T cell development has been investigated by generating gene-specific mutations in mice. Mutation of CD3 gamma, -delta, or zeta results in an incomplete block in development, characterized by reduced numbers of mature T cells that express low levels of TCR. In contrast, mature T cells are absent from CD3 epsilon(-/-) mice, and thymocyte development is arrested at the early CD4(-)CD8(-) stage, Although these results suggest that CD3 epsilon is essential for pre-TCR and TCR expression/function, their interpretation is complicated by the fact that expression of the CD3 gamma and CD3 delta genes also is reduced in CD3 epsilon(-/-) mice. Thus, it is unclear whether the phenotype of CD3 epsilon(-/-) mice reflects the collective effects of CD3 gamma, -delta, and -epsilon deficiency. By removing the selectable marker (PGH-NEO) from the targeted CD3 epsilon gene via Cre/loxP-mediated recombination, we generated mice that lack CD3 epsilon yet retain normal expression of the closely linked CD3 gamma and CD3 delta genes. These (CD3 epsilon(Delta/Delta)) mice exhibited an early arrest in T cell development, similar to that of CD3 epsilon(-/-) mice. Moreover, the developmental defect could be rescued by expression of a CD3 epsilon transgene. These results identify an essential role for CD3E in T cell development not shared by the CD3 gamma, CD3 delta, or zeta-family proteins and provide further evidence that PGK-NEO can influence the expression of genes in its proximity.