Imaging T Cell Airway Responses during Inflammation

肺是一个独特的上皮表面，吸入的颗粒，无论是惰性的，细菌还是病毒，都被困在非常接近血流的上皮表面上。这对免疫系统的T细胞提出了独特的空间挑战，以适当地调查这些抗原。像许多上皮组织一样，免疫巨噬细胞和树突细胞的选择在表面之内和之下准备吞噬和中和，或者诱导对侮辱的更深刻的反应。在包括过敏性以及细菌或病毒损伤的炎性损伤期间，肺微环境发生物理变化。 这个新的项目2将使用活肺和气道的实时成像来确定抗原如何进入肺并随后激活T细胞，将大部分精力集中在哮喘小鼠模型上。主要的问题是炎症环境如何产生一个反馈回路，促进加速免疫反应，从而增强炎症环境。我们假设肺气道和肺泡的炎症为T细胞过度反应创造了环境。 淋巴细胞引发这种环境反过来对突触相互作用是高度促进的，因此增加了肺重塑因子包括细胞因子的产生。我们认为，这有三个不同的组成部分。首先，在耐受性吞噬巨噬细胞和高免疫原性树突状细胞之间存在数量、定位、抗原摄取和运输特征的转变。炎症抗原的特征以及重塑环境的特征都被认为是直接的。 负责与T细胞相互作用的APC性质的转变。其次，局部多克隆和抗原特异性调节性T细胞的转变，部分由APC群体的变化调节，随后调节T细胞的活化。最后，T细胞和它们的APC通过由诸如肺支原体或肥大细胞耗竭的试剂诱导的气道重塑和炎症来调节。因此，炎症为对吸入抗原的反应创造了肥沃的刺激土壤。

The lung Is a unique epithelial surface at which inhaled particles, be they inert, bacteria or viral, are trapped in very close proximity to the bloodstream and in a filigree of epithelial surfaces. This presents unique spatial challenges for the T cells of the immune system to properly survey these antigens. Like many epithelial tissues, a selection of Immune macrophage and dendritic cells are poised within and beneath the surface to engulf and either neutralize, or to induce a more profound response to the Insult. During inflammatory insults including those of allergic but also bacterial or viral insults, the lung microenvironment physically changes. This new Project 2 will use live-imaging of viable lung and airways to determine how antigens traffic Into the lung and subsequently activate T cells, focusing the majority of effort upon a mouse model of asthma. The primary Issue being addressed is how inflammatory environments create a feedback loop that promotes accelerated immune responses and thus an enhanced inflammatory environment. We hypothesize that inflammation in the lung airway and aveolae creates a hyperreactive milieu for T lymphocyte priming. This milieu in turn is highly facilltative for synaptic interactions and thus increased production of lung remodeling factors Including cytokines. We propose that there are three distinct components of this. First, that there is a shift in the numbers, localization, antigen uptake and trafficking features between tolerizing phagocytic macrophages and highly immunogenic dendritic cells. The features of inflammatory antigens as well as the features of a remodeled milieu are both proposed to be directly responsible for the shift in the nature of APC which interact with T cells. Second, a shift In local polyclonal and antigen-specific regulatory T cells,modulated in part by the changes in APC population, subsequently modulates the activation of T cells. Finally, that T cells and their APC are modulated by airway remodeling and inflammation induced by agents such as Mycoplasma pulmonis or mast cell depletion. Thus, inflammation creates a fertile stimulatory ground for responses to inhaled antigens.