Innate mechanisms of regulation of Th17 responses

项目概要/摘要 典型微生物配体通过结合经典模式识别受体诱导炎症 (PRR)具有许多有益的结果，包括消除病原体和激活适应性 免疫力是防止再感染的一种保护。然而，不必要的炎症也可能是 由有毒物质（毒素、尿酸等）引起的PRR异常激活或由于天然 先天免疫系统的传感器或适配器发生突变，导致自身炎症 疾病如Cryopyrin相关的炎症性综合征和干扰素病。自身免疫 另一方面，疾病与自身炎症性疾病不同， 病理是自身反应性T和B细胞。自身免疫炎症可导致衰弱的结果 因为对肾脏、胰腺、肠道以及皮肤和关节等重要器官造成损害。 巧合的是，T细胞自身免疫性疾病的许多临床治疗都是针对 由先天免疫系统产生的炎性细胞因子。我们以前的工作表明，效应器 效应记忆CD 4 T细胞具有驱动IL-1b产生的能力，完全独立于 模式识别受体激活。我们发现效应CD 4 T细胞提供信号1和信号2。 IL-1b的产生依赖于TNF α和FasL的信号转导通路。 方式目前的建议是基于非常强的初步数据，表明效应CD 4 事实上，T细胞有能力模仿微生物配体，以驱动广泛的促炎程序， 先天免疫系统的细胞。我们发现，效应记忆CD 4 T细胞诱导额外的基因， 树突状细胞，建立与先天免疫系统的“T细胞指令”相关的重要问题。 在这里，我们证实，虽然PRR的近端激活是幼稚T细胞激活所必需的，但效应子T细胞的激活是必需的。 记忆性T细胞具有直接激活先天免疫系统的能力，从而绕过了免疫调节的需要。 PRR传感。尽管这可能已经进化为先天自适应串扰的有益部分，但我们 建议了解驾驶中先天免疫的适应性指导的有害结果 炎症和组织病理学。为了获得先天性炎症驱动的机制性理解， 通过效应CD 4 T细胞，我们提出了三个目标，其中1.我们将研究和描述 由不同的效应记忆T细胞谱系驱动的先天性炎症，并确定分子参与者 在这个过程中，2。我们将研究效应记忆CD 4 T细胞的分子机制， 细胞驱动先天性炎症，特别关注STING和DNA损伤; 3.我们将研究 CD 4 T细胞效应/效应记忆CD 4 T细胞驱动先天性炎症对自身免疫的影响 疾病和病理学。这些目标的成功实现将为T细胞驱动的免疫系统提供新的见解。 先天性炎症独立，并将开辟新的目标，以治疗自身免疫性疾病。

Project Summary/Abstract Induction of inflammation by canonical microbial ligands by engaging classical patten recognition receptors (PRR) has many beneficial outcomes including elimination of the pathogen and activation of adaptive immunity that serves as protection against reinfection. However, unwarranted inflammation can also be induced by aberrant activation of PRRs by noxious agents (toxins, uric acid etc) or because of naturally occurring mutations in sensors or adapters of the innate immune system leading to auto-inflammatory diseases such as Cryopyrin Associated Inflammatory Syndromes, and Interferonopathies. Auto-immune diseases on the other hand are different than auto-inflammatory diseases as the culprits that trigger pathology are self-reactive T and B cells. Auto-immune inflammation can lead to debilitating outcomes because of damage to vital organs such as kidney, pancreas intestines as well as Skin and joints. Paradoxically, many of the clinical treatments for T cell auto-immune diseases are all directed towards inflammatory cytokines made by the innate immune system. Our previous work demonstrated that effector and effector memory CD4 T cells have the capacity to drive IL-1b production, completely independent of pattern recognition receptor activation. We discovered that Effector CD4 T cells provide both signal 1 (TNFa) and signal 2 (FasL) to instruct the myeloid cells to produce IL-1b in a Caspase-8 dependent manner. The current proposal is based on very strong preliminary data that demonstrates that effector CD4 T cells in fact have the capacity to mimic microbial ligands to drive a broad pro-inflammatory program in cells of the innate immune system. We find that effector memory CD4 T cells induce additional genes in Dendritic cells that sets up important questions related to “T cell instruction” of the innate immune system. Here we posit that while proximal activation of PRRs is necessary for naïve T cell activation, effector memory T cells have the ability to directly activate the innate immune system thus bypassing the need for PRR sensing. Although this might have evolved as a beneficial arm of the innate adaptive cross-talk, we propose to understand the detrimental outcomes of adaptive instruction of innate immunity in driving inflammation and tissue pathology. In order to gain mechanistic understanding of innate inflammation driven by effector CD4 T cells, we propose three aims where 1. We will examine and characterize the nature of innate inflammation driven by different effector memory T cell lineages and identify the molecular players involved in this process, 2. We will investigate the molecular mechanisms by which effector memory CD4 T cells drive innate inflammation with a particular focus on STING and DNA damage and 3. We will examine the impact of CD4 T cell effector/effector memory CD4 T cell driven innate inflammation on auto-immune disease and pathology. Successful completion of these aims will provide novel insights into T cell driven innate inflammation independent and will open up new targets to treat auto-immune diseases.