CD28 plays a critical role in the segregation of PKCθ within the immunologic synapse
CD28 plays a critical role in the segregation of PKCθ within the immunologic synapse
复制标题
DOI：
10.1073/pnas.142298399
复制
发表时间：
2002-07-09
影响因子：
11.1
通讯作者：
Grey, HM
中科院分区：
文献类型：
--
作者：
Huang, JY;Lo, PF;Grey, HM
导致细胞蛋白定位于T细胞和抗原呈递细胞之间相互作用区域的信号传导途径以及这些分子进一步分选到免疫突触的外周超分子活化簇或中央超分子活化簇区域的机制知之甚少。在这项研究中，我们研究了CD 28共刺激在T细胞受体（TCR）介导的免疫突触形成方面的蛋白激酶C（PKC）θ定位的功能参与。我们发现，CD 3交联本身就足以诱导幼稚CD 4（+）T细胞中的PKC θ加帽。药理学抑制剂和基因敲除小鼠的研究表明，驱动PKC θ膜的TCR衍生信号。易位需要Src家族激酶Lck，但不需要Fyn。此外，对T细胞分子持续存在于免疫突触的时间过程研究表明，与TCR不同，PKC θ在突触中持续存在至少4小时，这一时间足以使T细胞致力于细胞分裂。最后，通过使用来自野生型或CD 28缺陷小鼠的TCR转基因T细胞，我们表明CD 28表达是形成成熟免疫突触所必需的，因为CD 28- T细胞的抗原刺激导致免疫突触中PKC θ和淋巴细胞功能相关抗原-1的弥漫性定位模式，与PKC θ在CD 28（+）T细胞中的中央超分子活化簇定位相反。
The signaling pathways that lead to the localization of cellular protein to the area of interaction between T cell and antigen-presenting cell and the mechanism by which these molecules are further sorted to the peripheral supramolecular activation cluster or central supramolecular activation cluster regions of the immunologic synapse are poorly understood. In this study, we investigated the functional involvement of CD28 costimulation in the T cell receptor (TCR)-mediated immunologic synapse formation with respect to protein kinase C (PKC)theta localization. We showed that CD3 crosslinking alone was sufficient to induce PKCtheta capping in naive CD4(+) T cells. Studies with pharmacologic inhibitors and knockout mice showed that the TCR-derived signaling that drives PKCtheta membrane. translocation requires the Src family kinase, Lck, but not Fyn. In addition, a time course study of the persistence of T cell molecules to the immunologic synapse indicated that PKCtheta, unlike TCR, persisted in the synapse for at least 4 h, a time that is sufficient for commitment of a T cell to cell division. Finally, by using TCR-transgenic T cells from either wild-type or CD28-deficient mice, we showed that CD28 expression was required for the formation of the mature immunologic synapse, because antigen stimulation of CD28- T cells led to a diffuse pattern of localization of PKCtheta and lymphocyte function-associated antigen-1 in the immunologic synapse, in contrast to the central supramolecular activation cluster localization of PKCtheta in CD28(+) T cells.