Role of Blimp1 (Prdm1) in lung immune responses and tolerance

项目总结 肺和上呼吸道是有规律地暴露于外界的粘膜表面。 环境。像身体的其他粘膜表面一样(例如，肠道和雌性生殖 呼吸道)肺和呼吸道的正常功能需要避免慢性炎症。这个 粘膜免疫动态平衡和对外源性刺激耐受的机制 表面是复杂的、多样的，而且人们对此知之甚少。在上一个资助期内，我们的研究 已经确定了受转录因子Blimp1(编码)调控的不同分子通路 通过Prdm1基因)，促进肠粘膜的免疫动态平衡，并可能 其他粘膜表面，如肺。我们发现Blimp1特别是 肠道调节性T淋巴细胞亚群的表达及Blimp1的表达 在这些细胞中被要求保持其调节属性并防止获得 炎性物质。此外，我们的研究表明，T细胞中缺乏Blimp1是 与炎性细胞因子IL9表达增加和气道恶化相关 发炎。在该奖项的资助期内，我们产生了一个新的敲击Blimp1 报告小鼠，允许可视化Blimp1在造血细胞中的表达 在包括环境表面在内的不同组织中处于稳定状态。这一新发现引导我们找到了 这一续签申请的基础是观察到Blimp1是结构性的 在肺泡巨噬细胞中的表达水平高于其他 肺和其他组织中的髓样细胞。更重要的是，我们发现Blimp1的缺失 在小鼠的巨噬细胞中，对引起肺炎的细菌的反应减弱 肺炎链球菌，导致炎症反应加剧，肺部恶化 组织损伤和细菌负荷增加。此外，我们确定了MHC II类和 调节分子CD200R1和IL10作为Blimp1在肺巨噬细胞中的可能靶点。 总之，这些观察结果导致了我们的假设，即Blimp1起着关键调节因子的作用 通过抑制两个淋巴器官的炎症活动来维持肺内免疫平衡 和髓系细胞。在这个提案中，我们将定义细胞和分子机制， Blimp1促进肺内免疫动态平衡。我们期待着实现以下目标 这项应用将揭示控制免疫反应和 肺部的耐受性，并将为开发新的治疗方法提供信息 慢性肺炎性疾病。

PROJECT SUMMARY The lungs and upper airways are mucosal surfaces that are regularly exposed to the external environment. Like other mucosal surfaces in the body (e.g. intestines, and female reproductive tract) proper functioning of the lungs and airways requires avoidance of chronic inflammation. The pathways underlying immune homeostasis and tolerance to exogenous stimuli at mucosal surfaces are complex, diverse and poorly understood. During the last funding period, our studies have identified different molecular pathways regulated by the transcription factor Blimp1 (encoded by the Prdm1 gene) that promote immune homeostasis in the intestinal mucosa and potentially other mucosal surfaces such as the lungs. We have discovered that Blimp1 is specifically expressed in a subset of regulatory T lymphocytes in the intestines and that expression of Blimp1 in these cells is required to maintain their regulatory properties and prevent acquisition of inflammatory properties. In addition, our studies revealed that lack of Blimp1 in T cells is associated with increased expression of the inflammatory cytokine IL9 and worsened airway inflammation. During the funding period of the award we generated a new knock-in Blimp1 reporter mouse that allowed visualization of Blimp1 expression in hematopoietic cells at the steady state in different tissues, including environmental surfaces. The new finding that led us to form the basis for this renewal application was the observation that Blimp1 is constitutively expressed in lung resident alveolar macrophages at higher levels than the observed in other myeloid cells in the lung and in other tissues. More importantly, we found that deletion of Blimp1 in macrophages in mice compromised the response against the pneumoniae-causing bacteria Streptococcus pneumoniae, leading to exacerbated inflammatory responses, worsened lung tissue damage and increased bacterial burden. Moreover, we identified MHC class II and the regulatory molecules CD200R1 and IL10 as putative targets of Blimp1 in lung macrophages. Together, these observations led to our hypothesis that Blimp1 functions as critical regulator to maintain immune homeostasis in the lungs by restraining inflammatory activity of both lymphoid and myeloid cells. In this proposal we will define the cellular and molecular mechanisms by which Blimp1 promote immune homeostasis in the lung. We anticipate that achievement of the goals of this application will uncover novel mechanisms underlying control of immune response and tolerance in the lungs and will inform the development of new therapeutic approaches to treat chronic lung inflammatory conditions.