Mechanism of basophil mediated immune modulation

描述（由申请人提供）：嗜碱性粒细胞现在被认为是Th 2介导的免疫应答（如过敏性炎症和寄生虫感染）中的关键效应子和免疫调节剂。有证据表明，嗜碱性粒细胞产生Th 2诱导因子，包括IL-4，Th 2免疫的标志性细胞因子，从而诱导活化的初始CD 4 T细胞的Th 2分化。然而，鉴于嗜碱性粒细胞大多数在稳态条件下在循环中发现，嗜碱性粒细胞如何促进Th 2分化仍然是未知的。最近的一项研究报道，嗜碱性粒细胞在变应原免疫后瞬时募集到引流淋巴结中，促进Th 2分化。与此一致，我们发现在寄生虫注射后，引流淋巴结中有短暂的嗜碱性粒细胞募集。有趣的是，IL-3在嗜碱性粒细胞募集中起关键作用，因为在注射寄生虫的IL-3 KO小鼠中不存在募集。过继转移的嗜碱性粒细胞的淋巴结进入被废除后，百日咳毒素治疗，表明参与趋化因子/趋化因子受体相互作用。共注射卵蛋白与寄生虫优先诱导OVA特异性IL-4产生T细胞免疫引流淋巴结内，强烈表明，招募嗜碱性粒细胞可能参与介导的Th 2免疫。基于这些结果，我们提出了这样的假设，即淋巴结内活化的T细胞产生的IL-3刺激IL-3R+靶细胞募集循环嗜碱性粒细胞，从而促进Th 2分化。两个具体目标将进行测试，以解决假设。目的#1将测试IL-3通过嗜碱性粒细胞募集对Th 2免疫的发展的贡献。目的#2将定义参与嗜碱性粒细胞淋巴结募集的IL-3的靶点。阐明嗜碱性粒细胞是如何被募集到组织如淋巴或发炎组织中的，将为理解嗜碱性粒细胞对Th 2免疫的发展以及嗜碱性粒细胞介导的病理学在变应性炎症包括哮喘中的体内贡献提供重要的见解。公共卫生相关性：越来越多的证据表明，嗜碱性粒细胞在过敏性炎症以及寄生虫感染中发现的2型介导的免疫应答中起关键作用。该建议旨在研究嗜碱性粒细胞调节免疫反应的机制。这些结果可能使我们能够更好地了解这些罕见但有效的细胞在体内的作用，并开发新的策略来预防嗜碱性粒细胞介导的病理学，这些病理学通常在过敏性炎症如哮喘中发现。

DESCRIPTION (provided by applicant): Basophils are now recognized as critical effectors and immune modulators during Th2 mediated immune responses, such as allergic inflammations and parasite infections. Evidence suggests that basophils produce Th2 inducing factors including IL-4, the signature cytokine of Th2 immunity, thus inducing Th2 differentiation of activated naive CD4 T cells. However, given that basophils are mostly found in the circulation during steady- state conditions, how basophils contribute to the Th2 differentiation remain unknown. A recent study reported that basophils are transiently recruited into the draining lymph nodes upon allergen immunization, promoting Th2 differentiation. Consistent with this, we found transient basophil recruitment into the draining lymph node following parasite injection. Interestingly, IL-3 plays a crucial role in basophil recruitment as the recruitment was absent in IL-3 KO mice injected with parasites. Lymph node entry of adoptively transferred basophils was abolished after treatment with pertussis toxin, suggesting the involvement of chemokine/chemokine receptor interaction. Coinjection of OVA protein with parasites preferentially induces OVA-specific IL-4 producing T cell immunity within the draining lymph nodes, strongly suggesting that recruited basophils may be involved in mediating the Th2 immunity. Based on these results, we propose the hypothesis that IL-3 produced by activated T cells within the lymph nodes stimulates IL-3R+ target cells to recruit circulating basophils, thus promoting Th2 differentiation. Two specific aims will be tested to address the hypothesis. Aim #1 will test the contribution of IL-3 to the developing Th2 immunity via basophil recruitment. Aim #2 will define targets of IL-3 involved in basophil lymph node recruitment. Elucidating how basophils are recruited into tissues such as lymphoid or inflamed tissues will provide critical insights into understanding in vivo contribution of basophils to developing Th2 immunity as well as to basophil mediated pathology found in allergic inflammation including asthma. PUBLIC HEALTH RELEVANCE: Evidence indicating that basophils play critical roles in type 2 mediated immune responses found in allergic inflammations as well as parasitic infections is increasing. This proposal aims to investigate poorly defined mechanism by which basophils modulate immune responses. The results may allow us to better understand in vivo roles of these rare yet potent cells and to develop novel strategies to prevent basophil mediated pathology often found in allergic inflammations such as asthma.