CD86 Signaling in B Cells

B细胞表面的CD86(B7-2)识别CD28并促进T细胞活化。最新数据 表明CD86也可以直接将信号传递到B细胞，以调节 产生了IgG1/IgG4，不影响类开关重组。的总目标是 本研究旨在确定CD86在小鼠或人身上的作用机制 B细胞促进抗体同种类型的增加，从而中和诸如 作为肺炎链球菌。使用CD86的小鼠过继转移模型- 缺乏B细胞，我们发现这些B细胞不能产生控制水平的 肺炎球菌多糖特异性IgG1或IgG3与野生型B细胞相比， 提示CD86在调节机体保护水平方面具有潜在的生理学作用 B细胞产生的抗体。CD86对CD40L/IL-4激活的原代B细胞的刺激作用 体外细胞被发现增加了PI3K的活性，CD19是一个潜在的联系 在这些事件之间。我们最近发现B细胞受体相关蛋白-37 (BAP37)，而不是CD19，与CD86从CH12.LX B细胞系免疫共沉淀， 而CD86胞浆结构域中的磷酸丝氨酸/苏氨酸缺失失败 阻断BAP37与CD86的结合，但减弱CD86诱导的功能 不影响CD40L/IL-4功能。总而言之，这些数据挑战了公认的 认为CD86只是CD28的识别分子，并强调需要 更好地了解近端信号转导机制，增强生理性 关联性。我们建议检验CD86刺激B细胞的假设 促进信号中间产物的激活，从而促进 在免疫球蛋白1水平上。拟议中的实验将确定信号中间体是否 被CD86刺激招募/激活以促进信号功能，如果特定的话 CD86的结构域和膜微环境在CD86的功能中起作用， 以及CD86识别与信号传递之间是否存在功能和生理上的相关性。 检验我们假设的意义在于CD86的一个独特功能，以及 将确定治疗的分子靶点，以缓解IgG1/ IgG4介导的对肺炎链球菌等感染性生物的保护作用 癌症患者的死因。

CD86 (B7-2) on a B cell recognizes CD28 and promotes T cell activation. Recent data show that CD86 may also mediate signals directly to a B cell to modulate the level of IgG1/IgG4 produced, without affecting class switch recombination. The overall goal of this research project is to identify the mechanism by which CD86 on a murine or human B cell promotes an increase in an Ab isotype that neutralizes infectious organisms such as Streptococcus pneumoniae. Using a murine adoptive transfer model with CD86- deficient B cells, we showed that these B cells were unable to produce a control level of pneumococcal polysaccharide-specific IgG1 or IgG3 when compared to wildtype B cells, suggesting a potential physiologic role for CD86 in modulating the level of protective antibody produced by a B cell. CD86 stimulation on a CD40L/IL-4-activated primary B cell in vitro was found to increase PI3K activity, with CD19 serving as a potential link between these events. We recently found that the B cell receptor-associated protein-37 (BAP37), but not CD19, immunoprecipitated with CD86 from the CH12.LX B cell line, and that phosphoserine/threonine deletions within the CD86 cytoplasmic domain failed to disrupt BAP37 association with CD86, but diminished CD86-induced function without affecting CD40L/IL-4 function. Collectively, these data challenge the accepted dogma that CD86 is only a recognition molecule for CD28, and emphasizes the need to better understand proximal signaling mechanisms and strengthen physiological relevance. We propose to test the hypothesis that CD86 stimulation on a B cell facilitates the activation of signaling intermediates that promote an increase in the level of IgG1. Proposed experiments will determine if a signaling intermediate is recruited/activated by CD86 stimulation to facilitate signaling function, if specific domains of CD86 and the membrane microenvironment play a role in CD86 function, and if there is functional and physiological relevance for CD86 recognition vs. signaling. The significance of testing our hypothesis is that a unique function for CD86, as well as molecular targets for therapeutics, will be identified to alleviate deficiencies in IgG1/ IgG4-mediated protection against infectious organisms such as S. pneumoniae, a leading cause of death in individuals with cancer.