Immune checkpoint modulation by bacterial metabolites.

摘要 本计画的目标是建立一套实验系统，以解读环境与生物技术的影响， 微生物衍生的芳烃受体（AHR）配体对围产期免疫系统的影响。AHR信号 已经显示在效应T细胞（Th 17，Th 22）和调节性T细胞的分化中起作用 （Foxp 3+和Tr 1）。在我们最近的研究中，我们证明了AHR信号传导在细胞凋亡中也起着至关重要的作用。 产生肥大细胞生长因子IL-9（Th 9）的人效应T细胞的发育。现在好了 确定微生物组来源的AHR配体在免疫稳态中起重要作用 微生物和宿主之间的联系这些AHR配体可以对T细胞功能具有深远的影响， 人体健康 在这个项目中，我们将破译微生物组和环境衍生的AHR配体如何改变细胞的功能。 T细胞在围产期条件下的反应。婴儿的免疫系统是高度致耐受性相比， 成人免疫系统这种免疫抑制状态是预防炎症和疾病所必需的。 出生后与环境微生物的接触，并建立与 浮游微生物因此，破坏了围产期免疫系统中的致耐受性环境， 可改变宿主免疫功能和抗原受体库。免疫库的变化 会反过来改变微生物的组成。这种效应可能会对 微生物组的组成，因此可能是改变健康发展起源的因素 疾病（doha）。 我们最近证明维生素D抑制AHR的表达。我们进一步 在活性维生素存在下活化的T细胞的表征表明，维生素D上调 免疫检查点分子CTLA 4和PD-L1。CTLA 4和PD-L1在T细胞中共表达， 具有免疫抑制功能的细胞。相反，用微生物来源的AHR配体刺激T细胞， 导致免疫检查点表达显著降低。总之，数据表明， 维生素D和AHR配体之间的关系可以决定T细胞活化和整体免疫的结果。 应答在本项目中，我们将建立两个实验系统来研究免疫检查点 通过微生物代谢物进行调节。一是系统研究免疫检查点调控 机制，另一个是确定维生素D和微生物来源的整体功能后果 AHR配体。该项目的完成将有助于阐明AHR配体对宿主的作用， 微生物/环境相互作用和人体免疫反应。

Abstract The goal of this project is to establish the experimental system to decipher the effect of environmental and microbe-derived aryl hydrocarbon receptor (AHR) ligands on the perinatal immune system. AHR signaling has been shown to play a role in the differentiation of both effector (Th17, Th22) and regulatory T cells (Foxp3+ and Tr1). In our recent study, we demonstrate that AHR signaling plays an essential role also in the development of human effector T cells that produce a mast cell growth factor IL-9 (Th9). It is now well established that microbiome-derived AHR ligands play significant roles in the immunological homeostasis between the microbes and the host. These AHR ligands can have a profound effect on T cell functions and human health. In this project, we will decipher how the microbiome and environment-derived AHR ligands change the response of T cells in the perinatal conditions. The infant immune system is highly tolerogenic compared to the adult immune system. This immunosuppressive state is needed to prevent inflammation and disease following the encounter with environmental microorganisms after birth and establish symbiotic conditions with commensal microorganisms. Hence, disruption of the tolerogenic environment in the perinatal immune system could change the host immune function and antigen receptor repertoire. Changes in the immune repertoire will alter the compositions of the microbiome in turn. The effect could have long-lasting influences on the compositions of the microbiome and hence can be a factor that changes the developmental original of health and disease (DOHaD). We have recently demonstrated that vitamin D suppresses the expression of AHR. Our further characterization of T cells activated in the presence of active vitamin showed that vitamin D upregulates immune checkpoint molecule CTLA4 and PD-L1. Co-expression of CTLA4 and PD-L1 was found among T cells with immunosuppressive functions. Conversely, stimulation of T cells with a microbe derived AHR ligand cause a marked decrease in immune checkpoint expression. Together, the data suggest that the balance between vitamin D and AHR ligand can dictate the outcomes of T cell activation and overall immune responses. In this project, we will establish two experiment systems to study the immune checkpoint modulation by microbial metabolites. One is the system to study the immune checkpoint regulation mechanism, the other is to determine the overall functional consequences of vitamin D and microbe-derived AHR ligands. Completion of this project will help to elucidate the AHR ligand effect on host- microbe/environment interactions and human immune responses.