Lantner Frida, Starlets Diana, Gore Yael, Flaishon Liat, Yamit-Hezi Ayala, Dikstein Rivka, Leng Lin, Bucala Richard, Machluf Yossy, Oren Moshe, Shachar Idit
Departments of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Blood. 2007 Dec 15;110(13):4303-11. doi: 10.1182/blood-2007-04-087486. Epub 2007 Sep 10.
Most mature follicular B cells circulate within the periphery in a quiescent state, without actively contributing to an acute immune response. Lasting B-cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. We recently demonstrated that cell surface CD74 controls mature B-cell survival. Stimulation of cell surface CD74 leads to NF-kappaB activation, which enables entry of the stimulated B cells into the S phase, induction of DNA synthesis, and cell division, and augments the expression of survival genes. In the present study, we investigated CD74 target genes to determine the identities of the molecules whose expression is modulated by CD74, thereby regulating B-cell survival. We report that CD74 activates the p65 member of the NF-kappaB family, which in turn up-regulates the expression of p53-related TAp63 proteins. TAp63 then binds and transactivates the Bcl-2gene and induces the production of Bcl-2 protein, thereby providing the cells with increased survival capacity. Thus, the CD74/NF-kappaB/TAp63 axis defines a novel antiapoptotic pathway in mature B cells, resulting in the shaping of both the B-cell repertoire and the immune response.
大多数成熟的滤泡B细胞在外周以静止状态循环，不积极参与急性免疫反应。外周B细胞的持久存在依赖于细胞表面受体转导的存活信号。我们最近证明细胞表面CD74控制成熟B细胞的存活。细胞表面CD74的刺激导致NF-κB激活，这使得受刺激的B细胞进入S期、诱导DNA合成和细胞分裂，并增强存活基因的表达。在本研究中，我们研究了CD74靶基因，以确定其表达受CD74调节从而调控B细胞存活的分子身份。我们报告CD74激活NF-κB家族的p65成员，进而上调p53相关TAp63蛋白的表达。然后TAp63结合并反式激活Bcl-2基因并诱导Bcl-2蛋白的产生，从而为细胞提供增强的存活能力。因此，CD74/NF-κB/TAp63轴定义了成熟B细胞中一条新的抗凋亡途径，导致B细胞库和免疫反应的形成。
