Medical Scientist Training Program and Immunology Graduate Program, University of Iowa, Iowa City, IA 52240, USA.
J Immunol. 2010 Dec 1;185(11):6555-62. doi: 10.4049/jimmunol.1000135. Epub 2010 Nov 1.
CD40 is required for T cell-dependent humoral immunity, but it can also contribute to the pathogenesis of autoimmunity and B cell malignancy. The TNFR-associated factor (TRAF)2 and TRAF6 adaptor proteins are positive regulators of CD40 signaling required to activate downstream kinase cascades and transcription factors. In contrast, TRAF3 can serve as a negative regulator of CD40 signaling, and CD40 signals are amplified in TRAF3(-/-) B cells. We previously reported a gain-of-function polymorphism of the human CD40 receptor, hCD40-P227A, which signals in an amplified manner to B lymphocytes. In this study, we show that hCD40-P227A binds more TRAF3 and TRAF5, as well as certain associated proteins, than wild-type-CD40. Studies in TRAF-deficient B cell lines revealed that hCD40-P227A uses TRAF3 as a positive rather than negative regulator. Although located outside of any known TRAF binding sites, the P227A polymorphism can alter TRAF binding and dramatically changes the role played by TRAF3 in CD40 signaling.
CD40 对于 T 细胞依赖性体液免疫是必需的，但它也可能导致自身免疫和 B 细胞恶性肿瘤的发病机制。TNFR 相关因子（TRAF）2 和 TRAF6 衔接蛋白是激活下游激酶级联和转录因子所需的 CD40 信号的正调节剂。相比之下，TRAF3 可以作为 CD40 信号的负调节剂，并且 TRAF3(-/-)B 细胞中的 CD40 信号被放大。我们之前报道了人类 CD40 受体 hCD40-P227A 的一种功能获得性多态性，该多态性以放大的方式向 B 淋巴细胞发出信号。在这项研究中，我们表明 hCD40-P227A 比野生型-CD40 结合更多的 TRAF3 和 TRAF5 以及某些相关蛋白。在 TRAF 缺陷型 B 细胞系中的研究表明，hCD40-P227A 将 TRAF3 用作正调节剂而不是负调节剂。尽管位于任何已知的 TRAF 结合位点之外，P227A 多态性可以改变 TRAF 结合，并极大地改变 TRAF3 在 CD40 信号中的作用。
