Innate Immunity and Allergy: Modulation by CTLA4

E免疫反应，包括由Toll样受体(TLR)4调节的免疫反应，为适应性过敏奠定了基础 免疫反应。我们的初步数据揭示了通过连接TLR4在肺中潜在的一种新的免疫途径 上调细胞毒性T淋巴细胞抗原4(CTLA4)的激活。我们证明了CTLA4信号可以 抑制实验性哮喘的过敏反应。具体地说，我们发现阻断CTLA4会增加过敏反应 炎症，而CTLA4的过度表达抑制过敏性炎症。有两条途径扩展了这些 调查结果。首先，天然的TLR4配体在体外和体内上调CTLA4，并抑制实验性哮喘； 与此观察一致的是，具有TLR4反应缺陷的TLR4突变小鼠具有增强的过敏性 回应。第二，通过CD45RB信号增加CTLA4，减少过敏反应。因为这三个分子 (CTLA4、TLR4和CD45RB)表达在T调节性(Tregs)细胞上，我们将研究Tregs在 TLR4和CD45Rb介导对实验性哮喘的抑制作用。 有趣的是，我们的初步数据还显示，作为TLR4配体的内毒素成分脂质A， 改善实验性哮喘。与我们的小鼠结果一致，流行病学研究表明，接触一种 富含内毒素的环境可降低儿童哮喘的风险。此外，在我们的模型中，Treg的耗尽 体内细胞增强过敏反应并阻断TLR4配体介导的对实验性哮喘的抑制。这些 结果表明，TLR4介导的哮喘抑制是通过表达Tregs的CTLA4介导的。因此，我们的 假设TLR4通过调节CTLA4的上调而减弱获得性免疫反应 抑制变态反应性炎症的关键途径。 目的研究CTLA4在抑制变态反应性炎症中的作用。 CTLA4(使用抗CTLA4抗体或缺陷小鼠)促进过敏性炎症，以及如何增加CTLA4 表达减少过敏性炎症(使用过表达CTLA4或CD45RB的CTLA4转基因 抗体)。目的2研究TLR4信号在体内是否调节CTLA4的表达。目标3将决定 TLR4信号抑制过敏性炎症的机制，包括细胞成分(APC，T细胞)， 以及CTLA4信号是否增强TLR4诱导的变态反应性炎症的抑制活性。目标4将决定 TLR4和CD45RB调节T细胞CTLA4表达的分子机制 CTLA4启动子区域。该项目的目标是通过以下方式确定新的途径和潜在的治疗靶点 先天免疫调节过敏性哮喘。

e immune responses, including those modulated by Toll-like receptor (TLR) 4 set the stage for the adaptive allergic immune response. Our preliminary data has uncovered a potential novel immune pathway in the lung by linking TLR4 activation with upregulation of cytotoxic T lymphocyte antigen 4 (CTLA4). We demonstrate that CTLA4 signals can inhibit allergic responses in experimental asthma. Specifically, we show that blocking CTLA4 increases allergic inflammation, whereas over expression of CTLA4 suppresses allergic inflammation. Two pathways extend these findings. First, innate TLR4 ligands upregulate CTLA4 both in vitro and in vivo and inhibit experimental asthma; and consistent with this observation, TLR4 mutant mice, which have deficient TLR4 responses, have enhanced allergic responses. Second, increased CTLA4, by CD45RB signals, decreases allergic responses. Because all three molecules (CTLA4, TLR4, and CD45RB) are expressed on T regulatory (Tregs) cells, we will investigate the function of Tregs in the TLR4 and CD45RB mediated inhibition of experimental asthma. Interestingly, our preliminary data also shows that the endotoxin component lipid A, which is a TLR4 ligand, ameliorates experimental asthma. Consistent with our murine results, epidemiological studies show that exposure to an endotoxin rich environment decreases the risk of childhood asthma. Furthermore, in our model, the depletion of Treg cells in vivo enhances allergic responses and blocks TLR4 ligand mediated inhibition of experimental asthma. These observations indicate that TLR4 mediated suppression of asthma is mediated by CTLA4 expressing Tregs. Thus, our hypothesis is that TLR4 attenuates the adaptive immune response by modulating upregulation of CTLA4, a critical pathway in the suppression of allergic inflammation. Aim I will characterize the role of CTLA4 in the suppression of allergic inflammationby determining how inhibition of CTLA4 (using anti-CTLA4 antibody or deficient mice) promotes allergic inflammation, and how increased CTLA4 expression decreases allergic inflammation (using CTLA4 transgenics that over express CTLA4, or CD45RB antibody). Aim 2 will investigate whether TLR4 signals modulate CTLA4 expression in vivo. Aim 3 will determine the mechanisms by which TLR4 signals suppress allergic inflammation, including the cellular components (APC, T cells), and whether CTLA4 signals enhance TLR4 induced suppressor activity in allergic inflammation. Aim 4 will determine the molecular mechanisms by which TLR4 and CD45RB regulate CTLA4 expression in T cells by analysis of the CTLA4 promoter region. The objective of this project is to identify novel pathways, and potential therapeutic targets by which innate immunity modulates allergic asthma.