Role of PI3-kinase in the development of mast cells and anti-helminth immunity

我们用p85α缺陷小鼠研究了IA类PI3K在肥大细胞分化中的作用，发现p85α缺陷小鼠选择性地缺乏胃肠道和腹膜肥大细胞，而肥大细胞在正常生理条件下很容易在皮肤等其他组织中发现。在p85α-缺陷小鼠中持续观察到强烈的被动全身性过敏反应，这表明这些小鼠的肥大细胞在功能上是正常的。缺乏c-Kit-PI3K信号通路似乎是p85α-缺陷小鼠肥大细胞独特发育障碍的机制，因为p85α-缺陷肥大细胞对SCF的增殖和JNK激活严重受损。由于SCF诱导的肥大细胞增殖需要JNK活性通过Rac1激活，JNK激活受损可能导致p85α-缺陷肥大细胞对SCF的有丝分裂能力缺陷。IA类PI3K对肥大细胞在t…More致病性免疫期的分化也是至关重要的。p85α-缺陷小鼠在委内瑞拉圆形线虫感染期间表现出严重的肥大细胞增生缺陷。p85α-缺陷小鼠肠系膜淋巴细胞IL-3产生受损可能是导致蠕虫感染时肥大细胞增生功能受损的主要缺陷。此外，p85α-缺陷小鼠的肠系膜淋巴细胞对寄生虫抗原产生的Th2细胞因子的反应显著受损。除了IL-3的产生受损外，其他Th2细胞因子的产生缺陷也可能影响肥大细胞增生，导致p85α-缺陷小鼠肠道线虫的清除延迟。事实上，用Th2细胞因子预处理的骨髓源肥大细胞而不是未经处理的肥大细胞的过继性转移能够将委内瑞拉葡萄球菌驱逐到野生型水平。进一步证明，在p85α-缺陷小鼠中，树突状细胞对微生物刺激的大量产生IL-12导致Th1反应增强。我们的数据显示，IA类PI3K在调节Th1和Th2应答之间的平衡中起着重要的作用，特别是在诱导或抑制Th2或Th1应答方面。在p85α-缺陷小鼠中，肥大细胞自主缺陷（c- kit介导的信号受损）和环境缺陷（Th1与Th2的异常倾斜）都可能导致肥大细胞增多缺陷和随后对肠道线虫感染的免疫反应受损。少

We examined the role of class IA PI3K in mast cell differentiation using p85α-deficient mice and found that p85α-deficient mice selectively lack gastrointestinal and peritoneal mast cells whereas mast cells are readily found in other tissues such as skin under normal physiological conditions. Strong passive systemic anaphylaxis was consistently observed in p85α-deficient mice, suggesting that mast cells in these mice are functionally competent. The lack of the c-Kit-PI3K signaling pathway seems the mechanism accounting for the unique developmental impairment of mast cells in p85α-deficient mice as proliferation and JNK activation in response to SCF was severely impaired in p85α-deficient mast cells. Since SCF-induced proliferation of mast cells requires JNK activity through Rac1 activation, impairment in JNK activation may cause the defective mitogenic capacity of p85α-deficient mast cells in response to SCF. The class IA PI3K is also critical for the differentiation of mast cells in t … More he pathogenic immune phase. The p85α-deficient mice demonstrated severe defects in mastocytosis during infection by Strongyloides venezuelensis. Impaired IL-3 production by mesenteric lymphocytes in p85α-deficient mice is likely the main defect leading to impaired mastocytosis during helminth infection. Furthermore, production of Th2 cytokines by mesenteric lymphocytes in response to the parasites' antigens was dramatically impaired in p85α-deficient mice. In addition to the impaired IL-3 production, defective production of other Th2 cytokines may influence mastocytosis, resulting in the delayed clearance of intestinal nematodes in p85α-deficient mice. Indeed, adoptive transfer of bone marrow-derived mast cells pretreated with Th2 cytokines but not untreated mast cells was able to restore the ability to expel S. venezuelensis to wild type levels. It was further demonstrated that hyperproduction of IL-12 by dendritic cells in response to microbial stimuli in p85α-deficient mice causes an enhanced Th1 response. Our data show that class IA PI3K plays an important role in the regulation of the balance between Th1 and Th2 responses, especially in the induction or suppression of Th2 or Th1 responses, respectively. In p85α-deficient mice, both mast cell autonomous (impaired c-Kit-mediated signal) and environmental (abnormal skewing of Th1 vs Th2) defects likely contribute to the defective mastocytosis and subsequent impairment in immune response against intestinal nematode infection. Less