Geiger T L, Leitenberg D, Flavell R A
Section of Immunobiology, and Department of Laboratory Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
J Immunol. 1999 May 15;162(10):5931-9.
The TCR complex signals through a set of 10 intracytoplasmic motifs, termed immunoreceptor tyrosine-based activation motifs (ITAMs), contained within the gamma-, delta-, epsilon-, and zeta-chains. The need for this number of ITAMs is uncertain. Limited and contradictory studies have examined the ability of subsets of the TCR's ITAMs to signal into postthymic primary T lymphocytes. To study signaling by a restricted set of ITAMs, we expressed in transgenic mice a chimeric construct containing the IAs class II MHC extracellular and transmembrane domains linked to the cytoplasmic domain of the TCR zeta-chain. Tyrosine phosphorylation and receptor cocapping studies indicate that this chimeric receptor signals T cells independently of the remainder of the TCR. We show that CD4+ and CD8+ primary T cells, as well as naive and memory T cells, are fully responsive to stimulation through the IAs-zeta receptor. Further, IAs-zeta stimulation can induce primary T cell differentiation into CTL, Th1, and Th2 type cells. These results show that the zeta-chain ITAMs, in the absence of the gamma, delta, and epsilon ITAMs, are sufficient for the activation and functional maturation of primary T lymphocytes. It also supports the isolated use of the zeta-chain ITAMs in the development of surrogate TCRs for therapeutic purposes.
TCR复合物通过一组10个胞质基序发出信号，这些基序称为基于免疫受体酪氨酸的激活基序（ITAM），包含在γ、δ、ε和ζ链中。对如此数量的ITAM的需求尚不确定。有限且相互矛盾的研究探讨了TCR的ITAM亚群向胸腺后初级T淋巴细胞发出信号的能力。为了研究由一组受限的ITAM发出的信号，我们在转基因小鼠中表达了一种嵌合构建体，该构建体包含与TCR ζ链的胞质结构域相连的II类MHC IAs细胞外和跨膜结构域。酪氨酸磷酸化和受体共帽研究表明，这种嵌合受体独立于TCR的其余部分向T细胞发出信号。我们表明，CD4+和CD8+初级T细胞，以及幼稚和记忆T细胞，对通过IAs-ζ受体的刺激完全有反应。此外，IAs-ζ刺激可诱导初级T细胞分化为CTL、Th1和Th2型细胞。这些结果表明，在没有γ、δ和ε ITAM的情况下，ζ链ITAM足以实现初级T淋巴细胞的激活和功能成熟。这也支持在开发用于治疗目的的替代TCR时单独使用ζ链ITAM。
