Role of Integrin alphaEbeta7 on Th2 Immune Responses

Th2细胞因子IL-4、5、9、10和粒细胞-巨噬细胞集落刺激因子以及Th1/2细胞因子IL-3被认为是病理性变态反应的重要标志。产生或受这些细胞因子调控的T细胞、嗜酸性粒细胞和肥大细胞的分化、募集和激活是这些反应的中心组成部分。在这里，我们定义了粘膜整合素αEbeta7在Th2偏向免疫反应中以前未被认识到的作用。这种整合素主要表达在粘膜T细胞上，并可在肥大细胞和某些树突状细胞上诱导，但在动物体内不表达。我们最近开发了一种AlphaE缺陷小鼠，与阻断抗AlphaE特异性单抗一起，揭示了这种整合素在Th2偏向的粘膜免疫反应中的重要作用。初步研究表明，与野生型(AlphaE+/+)小鼠相比，雾化吸入卵白蛋白后，AlphaE缺陷(AlphaE-/-)小鼠出现较少的肺部炎症和呼吸道过度活动。因此，在目标1中，这一发现将在近亲交配遗传背景的AlphaE+/+和AlphaE-/-小鼠中得到证实，并将扩展到比较淋巴细胞的定位和表型。在目标2中，将比较雾化吸入卵清蛋白后AlphaE-/-和AlphaE+/+小鼠选定T细胞亚群产生的T细胞因子，并将进行过继转移实验，以确定能够重建AlphaE-/-小鼠肺反应的T细胞亚群。这些研究将揭示αEbeta7在这种基于Th2 T细胞/嗜酸性粒细胞的炎症中的作用。在肺部炎症模型中，过敏反应中的肥大细胞成分并不容易研究。因此，利用蠕虫感染诱导T细胞依赖的反应性肥大细胞增殖的模型，我们发现αE缺陷小鼠的反应增强。在目标3中，将比较旋毛虫诱导的肥大细胞增殖在近亲交配遗传背景下的αE-/-和αE+/+小鼠，以及用抗αEbeta7抗体治疗后的αE+/+小鼠。这些研究有望证实αEbeta7及其表达细胞在反应性肥大细胞增生中的重要作用。此外，还将确定αE缺乏对旋毛虫诱导的肥大细胞前体细胞募集、粘膜肥大细胞迁移/分化或分辨率的影响。目的4通过对旋毛虫诱导的T细胞定位和细胞因子产生的改变进行比较研究，探讨其促进反应性肥大细胞增殖的机制，并进行过继转移研究，以确定是T细胞或肥大细胞上的αE缺乏还是两者共同作用导致旋毛虫诱导的反应性肥大细胞增殖。

Th2 cytokines interleukin (IL)-4, 5, 9, 10 and granulocyte macrophage-colony stimulating factor, and the Th1/2 cytokine IL-3 have been importantly implicated as characterizing the immune responses in pathological allergic conditions. The differentiation, recruitment and activation of T cells, eosinophils and mast cells that produce or are regulated by these cytokines represent central components of these responses. Here, we define a previously unappreciated role for the mucosal integrin alphaEbeta7 in Th2 biased immunological responses. This integrin in predominantly expressed on mucosal T cells and can be induced on mast cells and certain dendritic cells, but is otherwise not expressed in the animal. We recently developed an alphaE deficient mouse that, together with blocking anti-alphaE specific monoclonal antibodies, have revealed an important role for this integrin in Th2 biased mucosal immune responses. Preliminary studies revealed that alphaE deficient (alphaE-/-) mice developed less pulmonary inflammation and airway hyperactivity after aerosolized ovalbumin exposure than wildtype (alphaE+/+) mice. Thus, in Aim 1, this finding will be confirmed in alphaE+/+ and alphaE-/- mice on an inbred genetic background and in alphaE+/+ mice after treatment with an ani-alphaEbeta7 monoclonal antibody, and will be extended to compare lymphocyte localization and phenotype. In Aim 2, T lymphocyte cytokine production by selected T cell subsets will be compared after aerosolized ovalbumin exposure in alphaE-/- and alphaE+/+ mice, and adoptive transfer experiments will be performed to define T cell subpopulations that can reconstitute the pulmonary response in alphaE-/- mice. These studies will reveal the role of alphaEbeta7 in this Th2 T cell/eosinophil based inflammation. The mast cell component of the allergic response is not readily studied in the pulmonary inflammation model. Thus, using a helminth infection model that induced T cell dependent reactive mast cell hyperplasia, we found the response to be augmented in alphaE deficient mice. In Aim 3, Trichinella spiralis induced mast cell hyperplasia will be compared in alphaE-/- and alphaE+/+ mice on an inbred genetic background, and in alphaE+/+ mice after treatment with anti-alphaEbeta7 antibodies. These studies are expected to confirm the important role of alphaEbeta7, and the cells that express it, in reactive mast cell hyperplasia. In addition, the impact of alphaE deficiency on T. spiralis induced mast cell progenitor recruitment, mucosal mast cell migration/differentiation, or resolution will be defined. In Aim 4, a mechanism will be sought for the enhanced reactive mast cell hyperplasia through the comparative study of T. spiralis induced changes in T cell localization and cytokine production, and adoptive transfer studies will be performed to determine whether it is alphaE deficiency on the T cells or the mast cells or both that results in augmented T. spiralis induced reactive mast cell hyperplasia.