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发挥重要作用。然而，控制它们分化的分子机制在很大程度上是未知的。在对参与TR1细胞分化的信号通路进行研究的过程中，我们获得了初步的数据，证明芳烃受体(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细胞中的表达是由TR1促进的条件诱导的，并控制IL-10和自分泌的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IL10表达的转录因子。在体内，携带突变的AHR受体的小鼠表现出TR1细胞的生成受损。我们还发现，树突状细胞(DC)中AHR的激活触发了耐受性DC的分化，产生IL-10、IL-27和TGF21，支持TR1的分化，并抑制实验性自身免疫性脑脊髓炎(EAE)的发展。综上所述，这些结果表明T细胞和DC上的AHR信号在TR1细胞的分化过程中起着重要作用。我们假设AHR控制着TR1细胞的分化，而TR1细胞在控制炎症中起着至关重要的作用。为了解决我们的假设，我们将研究以下特定的目标：特异性目标1.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表达过程中的协同作用。特异性目的2.树突状细胞AHR信号如何促进TR1细胞分化？在这个目标中，我们将研究AHR激活诱导产生耐受性DC，DC促进TR1细胞的分化，但代价是极化Th1和Th17细胞的能力下降。特异性目的3：AHR信号是否控制体内TR1功能细胞的诱导？在这一目标中，我们将研究效应和调节性T细胞与DC在体内如何相互作用来控制实验性自身免疫性脑脊髓炎(EAE)。与公共卫生相关：旨在诱导和扩增TR1细胞的疗法很可能有利于治疗人类自身免疫性疾病，但控制TR1细胞分化的信号通路在很大程度上仍不清楚。基于我们对AHR信号在控制TR1细胞分化中的发现，靶向AHR为调控自身免疫性疾病的免疫反应提供了一条新的途径。

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.