Marinari Barbara, Costanzo Antonio, Marzano Valeria, Piccolella Enza, Tuosto Loretta
Department of Cellular and Developmental Biology, University of Rome La Sapienza, 00185 Rome, Italy.
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6098-103. doi: 10.1073/pnas.0308688101. Epub 2004 Apr 12.
CD28 is one of the most important costimulatory receptors necessary for full T lymphocyte activation. The CD28 receptor can enhance T cell antigen receptor (TCR) signals, as well as deliver independent signals. Indeed, CD28 engagement by B7 can generate TCR-independent signals leading to IkappaB kinase and NF-kappaB activation. Here we demonstrate that the TCR-independent CD28 signal leads to the selective transcription of survival (Bcl-xL) and inflammatory (IL-8 and B cell activation factor, but not proliferative (IL-2), genes, in a NF-kappaB-dependent manner. CD28-stimulated T cells actively secrete IL-8, and Bcl-xL up-regulation protects T cells from radiation-induced apoptosis. The transcription of CD28-induced genes is mediated by the specific recruitment of RelA and p52 NF-kappaB subunits to target promoters. In contrast, p50 and c-Rel, which preferentially bind NF-kappaB sites on the IL-2 gene promoter after anti-CD3 stimulation, are not involved. Thus, we identify CD28 as a key regulator of genes important for both survival and inflammation.
CD28是完全激活T淋巴细胞所必需的最重要的共刺激受体之一。CD28受体可增强T细胞抗原受体（TCR）信号，并传递独立信号。事实上，B7与CD28结合可产生不依赖TCR的信号，导致IκB激酶和NF-κB激活。在此我们证明，不依赖TCR的CD28信号以NF-κB依赖的方式导致存活基因（Bcl-xL）和炎症基因（IL-8和B细胞活化因子，但不包括增殖基因（IL-2））的选择性转录。CD28刺激的T细胞可主动分泌IL-8，Bcl-xL的上调可保护T细胞免受辐射诱导的凋亡。CD28诱导基因的转录是通过RelA和p52 NF-κB亚基特异性募集到靶启动子来介导的。相反，抗CD3刺激后优先结合IL-2基因启动子上NF-κB位点的p50和c-Rel则不参与此过程。因此，我们确定CD28是对存活和炎症都很重要的基因的关键调节因子。
