Mechanism of basophil mediated immune modulation

描述(申请人提供)：嗜碱性粒细胞现在被认为是Th2介导的免疫反应的关键效应器和免疫调节器，如过敏性炎症和寄生虫感染。有证据表明，嗜碱性粒细胞产生Th2诱导因子，包括Th2免疫的标志性细胞因子IL-4，从而诱导活化的初始CD4T细胞分化为Th2。然而，考虑到嗜碱性粒细胞主要是在稳态条件下在循环中发现的，嗜碱性粒细胞如何对Th2分化起作用仍不清楚。最近的一项研究报道，在过敏原免疫后，嗜碱性粒细胞瞬间被招募到引流淋巴结，促进Th2分化。与此一致，我们发现在注射寄生虫后，短暂性嗜碱性粒细胞重新聚集到引流淋巴中。有趣的是，IL-3在嗜碱性细胞募集中起着关键作用，因为在注射了寄生虫的IL-3KO小鼠中没有募集。经百日咳毒素处理后，过继转移的嗜碱性粒细胞的淋巴进入消失，提示趋化因子/趋化因子受体相互作用。OVA蛋白与寄生虫共注射可优先诱导引流淋巴结内OVA特异性IL-4产生T细胞免疫，强烈提示嗜碱性粒细胞可能参与了Th2免疫。基于这些结果，我们提出了一个假设，即淋巴结内活化的T细胞产生的IL-3刺激IL-3R+靶细胞招募循环中的嗜碱性粒细胞，从而促进Th2分化。为了解决这一假设，将测试两个具体目标。目的研究IL-3通过嗜碱性粒细胞募集在Th2免疫中的作用。目的#2将确定IL-3参与嗜碱性粒细胞淋巴招募的靶点。阐明嗜碱性粒细胞如何被募集到淋巴组织或炎症组织等组织中，将为了解嗜碱性粒细胞在体内对Th2免疫发育的贡献以及在包括哮喘在内的过敏性炎症中发现的嗜碱性粒细胞介导的病理提供重要的见解。与公共卫生相关：证据表明，嗜碱性粒细胞在过敏性炎症和寄生虫感染中发现的2型介导的免疫反应中发挥关键作用的证据正在增加。这项提议旨在研究嗜碱性粒细胞调节免疫反应的模糊机制。这一结果可能会让我们更好地了解这些稀有但强大的细胞在体内的作用，并开发新的策略来预防哮喘等过敏性炎症中常见的嗜碱性粒细胞介导的病理。

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.