INTEGRIN CD103-ROLE IN TH2 PULMONARY IMMUNE RESPONSES

哮喘是一种影响全球数百万人的疾病，是一种以呼吸道炎症和呼吸道高反应性为特征的复杂炎症性疾病。虽然多种分子信号和细胞参与了哮喘的发病机制，但已有研究表明，CD4+T淋巴细胞在哮喘发病中起着关键作用。具体地说，以分泌Th2细胞因子为特征的CD4+T辅助细胞。然而，幼稚T辅助细胞分化为Th2表型的免疫学途径尚不清楚。整合素αE(CD103)β7在淋巴细胞、树突状细胞和肥大细胞上表达，这些细胞类型与哮喘和粘膜免疫反应的动态调节有关。在以高Th2细胞因子水平、气道高反应性和肺部炎症为特征的小鼠气道高反应性体内模型中，研究了整合素αEbeta7在肺变态反应性炎症和气道反应性中的作用。整合素αE缺陷小鼠的肺部炎症、呼吸道反应性和Th2细胞因子水平显著降低。体外研究表明，来自AlphaE缺陷小鼠的未分离的脾细胞产生的Th2细胞因子水平显著低于AlphaE+/+小鼠。使用来自AlphaE缺陷和野生型小鼠的脾CD4+T细胞和辅助细胞的纯化群体进行的混合研究，将CD4+T细胞分化为Th2表型的调节定位于辅助细胞群体。鉴于25%的脾树突状细胞表达α-Ebeta7，提出了整合素α-Ebeta7在调节由α-Ebeta7树突状细胞介导的CD4+T细胞表型发育中起关键作用的假说。为了验证这一假设，将进行体外研究，以证明αEbeta7+树突状细胞在CD4+T细胞向Th2表型分化中的作用，并表征其表型和功能特征。将进行过继转移实验，以确定αEbeta7+树突状细胞在体内介导Th2极化的能力，以及在应对雾化抗原攻击时引发呼吸道高反应和肺部炎症的能力。此外，还将探讨树突状细胞上该整合素的表达对初始辅助性T细胞分化和Th2肺免疫反应的影响。这些研究可能对整合素αEbeta7在辅助性T细胞分化和树突状细胞生物学中的作用提供重要的见解。

Asthma, a disease which affects millions worldwide, represents a complex inflammatory disorder characterized by airway inflammation and airway hyperreactivity. Although multiple molecular signals and cells are involved in the pathogenesis of asthma, the CD4+ T lymphocyte has been clearly shown to play a critical role. Specifically, CD4+ T helper cells which are characterized by the secretion of Th2 cytokines. The immunologic pathways by which naive T helper cells differentiate into a Th2 phenotype, however, have yet to be clearly delineated. Integrin alphaE(CD103)beta7 is expressed on lymphocytes, dendritic cells and mast cells, cell types which have been implicated in asthma and the dynamic regulation of mucosal immune responses. The role of integrin alphaEbeta7 in the mediation of pulmonary allergic inflammation and airway reactivity was studied in an in vivo murine model of airway hyperresponsiveness, characterized by high levels of Th2 cytokines, airway hyperresponsiveness and pulmonary inflammation. Integrin alphaE deficient mice were found to have decreased pulmonary inflammation, airway reactivity and markedly reduced levels of Th2 cytokines. In vitro studies demonstrated unfractionated splenocytes from alphaE deficient mice produced significantly lower levels of Th2 cytokines than alphaE+/+ mice. Mixing studies, using purified populations of splenic CD4+ T cells and accessory cells from alphaE deficient and wild type mice, localized the regulation of CD4+ T cell differentiation to a Th2 phenotype to the accessory cell population. Given that alphaEbeta7 is expressed on 25 percent of splenic dendritic cells, the hypothesis that integrin alphaEbeta7 plays a critical role in the regulation of the phenotypic development of CD4+ T cells, mediated by alphaEbeta7 dendritic cells, was developed. To test this hypothesis, in vitro studies will be performed to demonstrate the role of alphaEbeta7+ dendritic cells in the differentiation of CD4+ T cells to a Th2 phenotype and to characterize their phenotypic and functional characteristics. Adoptive transfer experiments will be performed to determine the ability Of alphaEbeta7+ dendritic cells to mediate Th2 polarization in vivo and to confer airway hyperresponsiveness and pulmonary inflammation in response to aerosolized antigen challenge. The mechanisms by which expression of this integrin on dendritic cells mediates the differentiation of nave T helper cells and Th2 pulmonary immune responses will also be examined. These studies may provide significant insights into the role of integrin alphaEbeta7 in T helper cell differentiation and dendritic cell biology.