Role of aryl hydrocarbon receptor in IL-10 producing Tr1 regulatory cells

描述（由申请人提供）：产生IL-10的调节性1型（Tr 1）T细胞有助于调节自身免疫和移植物抗宿主病。然而，控制其分化的分子机制在很大程度上是未知的。在我们研究Tr 1细胞分化过程中所涉及的信号通路的过程中，我们获得了初步的数据，这些数据表明芳烃受体（AHR）在Tr 1细胞的分化过程中起着重要作用。我们发现，AHR的表达诱导T细胞的Tr 1促进条件，并控制IL-10和自分泌Tr 1生长因子IL-21的合成。此外，我们发现在Tr 1细胞中，AHR与c-Maf相互作用，c-Maf是一种已知控制T细胞中IL 10表达的转录因子。在体内，携带突变AHR受体的小鼠显示Tr 1细胞的生成受损。我们还发现，树突状细胞（DC）中的AHR激活触发致耐受性DC的分化，产生IL-10，IL- 27和TGF-21，支持Tr 1分化并抑制实验性自身免疫性脑脊髓炎（EAE）的发展。总之，这些数据表明T细胞和DC上的AHR信号在Tr 1细胞的分化过程中起重要作用。我们假设AHR控制Tr 1细胞的分化，Tr 1细胞在炎症控制中起着至关重要的作用。为了解决我们的假设，我们将研究以下具体目标：具体目标1。T细胞中的AHR信号如何促进Tr 1细胞的分化？我们将研究AHR与STAT蛋白的相互作用以及c-Maf和AHR在控制IL 10和自分泌生长因子IL 21表达过程中的合作。具体目标2. DC中的AHR信号如何促进Tr 1细胞的分化？在这个目标中，我们将研究通过AHR活化诱导致耐受性DC，DC以降低活化Th 1和Th 17细胞的能力为代价促进Tr 1细胞的分化。具体目标3. AHR信号传导是否控制体内功能性Tr 1细胞的诱导？在这个目的中，我们将研究如何在体内效应和调节性T细胞和DC相互作用，以控制实验性自身免疫性脑脊髓炎（EAE）。与公共卫生的相关性：旨在诱导和扩增Tr 1细胞的疗法可能有利于治疗人类自身免疫性疾病，但控制Tr 1细胞分化的信号通路在很大程度上仍然未知。基于我们对AHR信号在控制Tr 1细胞分化中的发现，靶向AHR提供了一种操纵自身免疫性疾病中免疫应答的新途径。 公共卫生相关性：自身免疫性疾病，如多发性硬化症，1型糖尿病和类风湿性关节炎是由免疫系统的不受控制的活动引起的。我们将研究一种叫做芳香烃受体的蛋白质是如何控制免疫系统的，以及如何影响它来改善多发性硬化症的动物模型。

DESCRIPTION (provided by applicant): IL-10 producing regulatory type 1 (Tr1) T cells are instrumental in the regulation of autoimmunity and graft versus host disease. However, the molecular mechanisms controlling their differentiation are largely unknown. During the course of our studies to investigate the signaling pathways involved in the differentiation of Tr1 cells we obtained preliminary data which demonstrate that the Aryl Hydrocarbon Receptor (AHR) plays an important role during the differentiation of Tr1 cells. We found that AHR expression is induced in T cells by Tr1- promoting conditions, and controls the synthesis of IL-10 and the autocrine Tr1 growth factor IL-21. Moreover, we found that in Tr1 cells, AHR interacts with c-Maf, a transcription factor known to control il10 expression in T cells. In vivo, mice carrying a mutant AHR receptor show and impaired generation of Tr1 cells. We also found that AHR activation in dendritic cells (DC) triggers the differentiation of tolerogenic DC that produce IL-10, IL- 27 and TGF21, support Tr1 differentiation and suppress the development of experimental autoimmune encephalomylelitis (EAE). All in all, these data suggest that AHR signaling on T cells and DC plays an important role during the differentiation of Tr1 cells. We hypothesize that AHR controls the differentiation of Tr1 cells which play a crucial role in the control of inflammation. To address our hypothesis we will investigate the following Specific Aims: SPECIFIC AIM 1. How does AHR signaling in T cells promote the differentiation of Tr1 cells? We will study the interaction of AHR with STAT proteins and the cooperation of c-Maf and AHR during the control of the expression of il10 and the autocrine growth factor il21. SPECIFIC AIM 2. How does AHR signaling in DC promote the differentiation of Tr1 cells? In this aim we will study the induction of tolerogenic DC by AHR activation, DC that promote the differentiation of Tr1 cells at the expense of a decreased ability to polarize Th1 and Th17 cells. SPECIFIC AIM 3. Does AHR signaling control the induction of functional Tr1 cells in vivo? In this Aim, we will study how effector and regulatory T cells and DC interact in vivo to control experimental autoimmune encephalomyelitis (EAE). Relevance to public health: Therapies aimed at the induction and expansion of Tr1 cells are likely to be beneficial for the treatment of human autoimmune disorders, but the signaling pathways that control the differentiation of Tr1 cells are still largely unknown. Based on our findings on AHR signaling in the control of Tr1 cell differentiation, targeting of AHR provides a new avenue to manipulate the immune response in autoimmune diseases. PUBLIC HEALTH RELEVANCE: Autoimmune diseases such as multiple sclerosis, type 1 diabetes and rheumatoid arthritis are caused by the uncontrolled activity of the immune system. We will investigate how a protein called Aryl Hydrocarbon Receptor controls the immune system and how affecting it ameliorates an animal model of multiple sclerosis.