CD86 Signaling in B Cells

B细胞上的CD 86（B7-2）识别CD 28并促进T细胞活化。最近的数据 显示CD 86也可直接介导信号至B细胞以调节 产生IgG 1/IgG 4，而不影响类别转换重组。的总目标 本研究项目旨在确定小鼠或人类CD 86表达的机制， B细胞促进中和感染性生物体的Ab同种型的增加， 肺炎链球菌使用小鼠过继转移模型， 缺陷型B细胞，我们发现这些B细胞不能产生对照水平的 当与野生型B细胞相比时， 提示CD 86在调节保护性T细胞水平中具有潜在的生理作用。 由B细胞产生的抗体。CD 86对CD 40 L/IL-4活化的原代B的刺激 发现体外培养的细胞增加PI 3 K活性，CD 19作为一个潜在的联系 这些事件之间。我们最近发现B细胞受体相关蛋白37 （BAP 37），而不是CD 19，与来自CH 12. LX B细胞系的CD 86免疫沉淀， CD 86胞质结构域内的磷酸丝氨酸/苏氨酸缺失 破坏BAP 37与CD 86的结合，但减弱CD 86诱导的功能 而不影响CD 40 L/IL-4功能。总的来说，这些数据挑战了公认的 CD 86只是CD 28的识别分子，并强调需要 更好地了解近端信号机制，加强生理 本案无关我们建议检验CD 86对B细胞的刺激 促进信号传导中间体的激活， 在IgG 1水平。建议的实验将确定信号传导中间体是否是 通过CD 86刺激招募/激活，以促进信号传导功能，如果特异性 CD 86的结构域和膜微环境在CD 86功能中起作用， 以及CD 86识别与信号传导是否存在功能和生理相关性。 检验我们假设的意义在于，CD 86的独特功能，以及 将鉴定用于治疗的分子靶点，以减轻IgG 1/ IgG 4介导的对感染性生物体如S.肺炎，一种主要的 癌症患者的死亡原因

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.