The cytoplasmic domain of CD28 is both necessary and sufficient for costimulation of interleukin-2 secretion and association with phosphatidylinositol 3'-kinase.
The cytoplasmic domain of CD28 is both necessary and sufficient for costimulation of interleukin-2 secretion and association with phosphatidylinositol 3'-kinase.
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CD28 的胞质结构域对于白细胞介素 2 分泌的共刺激以及与磷脂酰肌醇 3-激酶的关联是必要且充分的。
DOI：
10.1128/mcb.14.5.3392-3402.1994
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发表时间：
1994
影响因子：
5.3
通讯作者：
Weiss,A
中科院分区：
文献类型：
--
作者：
Stein,PH;Fraser,JD;Weiss,A
T细胞的激活需要两个信号事件。一种是通过T细胞抗原受体的结合来提供的，第二种是由抗原提呈细胞提供的共刺激信号。CD28通过与其配体B7-1和B7-2结合在抗原提呈细胞上介导共刺激信号，但CD28激活的信号通路尚未确定。在活化的T细胞上表达的同源分子CTLA-4也与B7-1和B7-2结合，但它是否具有信号功能尚不清楚。我们对CD28进行了结构-功能分析，以确定激活信号转导的功能结构域。40个氨基酸的CD28胞浆尾巴的截断取消了共刺激信号。含有CD8胞外区和跨膜区的嵌合载体与CD28的胞内区相连，具有共刺激信号功能。含有CTLA-4胞质尾巴的类似嵌合体没有信号。因此，CD28的细胞质区域，而不是CTLA-4，足以介导共刺激信号。此外，经CD28刺激后，CD28免疫沉淀物中有磷脂酰肌醇3‘-激酶P85亚基和磷脂酰肌醇3’-激酶活性。具有共刺激信号功能的CD8-CD28嵌合体与P85相关，而无功能的CD8-CTLA-4嵌合体和CDS-ζ嵌合体与P85无关。这些结果表明，磷脂酰肌醇3‘-激酶被CD28特异性激活，并可能介导CD28调控的共刺激信号通路中的近端事件。
T-cell activation requires two signaling events. One is provided by the engagement of the T-cell antigen receptor, and the second represents a costimulatory signal provided by antigen-presenting cells. CD28 mediates a costimulatory signal by binding its ligands, B7-1 and B7-2, on antigen-presenting cells, but the signaling pathway activated by CD28 has not been identified. A homologous molecule, CTLA-4, expressed on activated T cells, also binds to B7-1 and B7-2, but whether it has a signaling function is not known. We performed a structure-function analysis of CD28 to identify the functional domain which activates signal transduction. Truncation of the 40-amino-acid CD28 cytoplasmic tail abrogated costimulatory signaling. Chimeric constructs containing the extracellular and transmembrane regions of CD8 linked to the cytoplasmic region of CD28 had a costimulatory signaling function. Similar chimeras containing the cytoplasmic tail of CTLA-4 did not signal. Thus, the cytoplasmic region of CD28, but not CTLA-4, is sufficient to mediate costimulatory signaling. In addition, after CD28 stimulation, the p85 subunit of phosphatidylinositol 3′-kinase and phosphatidylinositol 3′-kinase activity were found in CD28 immunoprecipitates. The CD8-CD28 chimera, which has a costimulatory signaling function, associates with p85, while the nonfunctioning CD8-CTLA-4 chimera and a CDS-ζ chimera do not associate with p85. These results suggest that phosphatidylinositol 3′-kinase is specifically activated by CD28 and may mediate proximal events in the costimulatory signaling pathway regulated by CD28.