Indirect recruitment of a CD40 signaling pathway in dendritic cells by B7-DC cross-linking antibody modulates T cell functions.
Indirect recruitment of a CD40 signaling pathway in dendritic cells by B7-DC cross-linking antibody modulates T cell functions.
复制标题
DOI：
10.1371/journal.pone.0005373
复制
发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Pease LR
中科院分区：
文献类型：
--
作者：
Radhakrishnan S;Cabrera R;Bruns KM;Van Keulen VP;Hansen MJ;Felts SJ;Pease LR
人类 IgM B7-DC XAb 在治疗和预防环境中均可保护小鼠免受肿瘤侵害。其作用机制是通过与树突状细胞 (DC) 表面的 B7-DC/PD-L2 分子结合来介导，从而诱导多分子帽并随后激活信号级联，从而确定 DC 表型的独特组合。其中一种表型，即 B7-DC XAb 诱导的 mTLR 成熟 DC 中的抗原积累，与 TREM-2 的信号传导有关，但对于动物模型中的治疗效果至关重要的其他 DC 表型所需的信号仍不清楚。在这里，FRET 和免疫共沉淀研究表明 CD40 被 B7-DC XAb 招募到多分子复合物中。来自 CD40 的信号很重要，因为用 B7-DC XAb (DCXAb) 处理的 CD40−/− DC 会激活 DAP12，但无法激活 NFκB，并且在细胞因子撤除或用维生素 D3 处理后无法避免细胞死亡。 CD40−/− DCXAb 也无法分泌 IL-6，并且无法支持 T 调节细胞在体外转化为 IL-17+ 效应 T 细胞。重要的是，CD40 的表达是 B7-DC XAb 诱导抗肿瘤 CTL 的整体能力所必需的，以提供针对多种肿瘤类型的保护，并使 DCXAb 成为体内有效的抗肿瘤疫苗。这些结果表明，B7-DC XAb 对 DC 表型的调节是通过其通过靶向结合细胞特异性表面决定簇来间接招募常见信号分子及其内源信号通路元件的能力。
The human IgM B7-DC XAb protects mice from tumors in both therapeutic and prophylactic settings. Its mechanism of action is mediated by its binding to B7-DC/PD-L2 molecules on the surface of dendritic cells (DCs) to induce a multimolecular cap and subsequent activation of signaling cascades that determine a unique combination of DC phenotypes. One such phenotype, the B7-DC XAb-induced antigen accumulation in mTLR-matured DCs, has been linked to signaling through TREM-2, but the signals required for other DC phenotypes critical for the therapeutic effects in animal models remain unclear. Here, FRET and co-immunoprecipitation studies show that CD40 is recruited to the multi-molecular complex by B7-DC XAb. Signals emanating from CD40 are important, as CD40−/− DCs treated with B7-DC XAb (DCXAb) activated DAP12, but failed to activate NFκB, and were not protected from cell death upon cytokine withdrawal or treatment with Vitamin D3. CD40−/− DCXAb also failed to secrete IL-6 and were unable to support the conversion of T regulatory cells into IL-17+ effector T cells in vitro. Importantly, the expression of CD40 was required for the overall ability of B7-DC XAb to induce anti-tumor CTL, to provide protection from a number of tumor types, and for DCXAb to be effective anti-tumor vaccines in vivo. These results indicate that B7-DC XAb modulation of DC phenotypes is through its ability to indirectly recruit common signaling molecules and elements of their endogenous signaling pathways through targeted binding to a cell-specific surface determinant.
登录
查看更多内容
影响因子：
5.4
作者：
Heckman, Karin L.;Schenk, Erin L.;Pease, Larry R.
通讯作者：
Pease, Larry R.
影响因子：
11.2
作者：
Pavelko, Kevin D.;Heckman, Karin L.;Pease, Larry R.
通讯作者：
Pease, Larry R.
影响因子：
11.2
作者：
Radhakrishnan, S;Nguyen, LT;Pease, LR
通讯作者：
Pease, LR
影响因子：
5.4
作者：
Benson, Rebecca J.;Hostager, Bruce S.;Bishop, Gail A.
通讯作者：
Bishop, Gail A.
影响因子：
4.4
作者：
Block, MS;Johnson, AJ;Pease, LR
通讯作者：
Pease, LR