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（Tr1） T细胞在自身免疫和移植物抗宿主病的调节中起重要作用。然而，控制它们分化的分子机制在很大程度上是未知的。在我们研究Tr1细胞分化过程中的信号通路的过程中，我们获得了初步的数据，证明芳烃受体（Aryl Hydrocarbon Receptor， AHR）在Tr1细胞的分化过程中起着重要的作用。我们发现，AHR在T细胞中通过Tr1促进条件诱导表达，并控制IL-10和自分泌Tr1生长因子IL-21的合成。此外，我们发现在Tr1细胞中，AHR与c-Maf相互作用，c-Maf是一种已知控制T细胞中il10表达的转录因子。在体内，携带突变AHR受体的小鼠表现出Tr1细胞的产生受损。我们还发现，树突状细胞（DC）中的AHR激活可触发耐受性DC的分化，产生IL-10、IL- 27和TGF21，支持Tr1分化并抑制实验性自身免疫性脑脊髓炎（EAE）的发展。综上所述，这些数据表明，T细胞和DC上的AHR信号在Tr1细胞的分化过程中发挥了重要作用。我们假设AHR控制Tr1细胞的分化，而Tr1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，我们将调查以下具体目标：T细胞中的AHR信号如何促进Tr1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il10和自分泌生长因子il21表达中的协同作用。具体目标2。DC中的AHR信号如何促进Tr1细胞的分化？在这个目的中，我们将研究通过AHR激活诱导耐受性DC， DC促进Tr1细胞的分化，以降低Th1和Th17细胞极化能力为代价。具体目标3。AHR信号是否在体内控制功能性Tr1细胞的诱导？在本研究中，我们将研究效应T细胞和调节性T细胞如何在体内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Tr1细胞的疗法可能对治疗人类自身免疫性疾病有益，但控制Tr1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Tr1细胞分化中的发现，靶向AHR为操纵自身免疫性疾病的免疫反应提供了新的途径。

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.