UNDERSTANDING AUTOREACTIVE T CELL PATHOGENICITY

描述（由申请人提供）：CD 4 T辅助（TH）细胞通过产生促炎细胞因子驱动自身免疫。控制自身反应性T细胞的细胞因子产生和致病性的分子决定因素仍不清楚。在实验性自身免疫性脑脊髓炎（EAE）中，TH 1、TH 17浸润中枢神经系统（CNS）。值得注意的是，IFN-γ和IL-17，TH 1和TH 17谱系产生的标志性细胞因子，不是致脑炎所必需的。相反，TH细胞衍生的细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF，由Csf 2编码）在介导神经炎症中起非冗余作用。自身反应性T细胞产生的免疫抑制细胞因子，包括IL-10，也影响T细胞致脑炎性。我们已经发现，转录因子Bhlhe 40缺陷的小鼠对EAE的诱导具有抗性。Bhlhe 40-/- TH细胞产生正常量的标志性细胞因子，但产生减少量的GM-CSF和增加量的IL-10。我们将测试的中心假设，Bhlhe 40是一个必要的决定因素的自身反应性T细胞的致病性。在目的1中，我们将确定Bhlhe 40在神经炎症中功能的机制基础，测试Bhlhe 40-/- T细胞的非致脑炎性是由于其细胞内在IL-10产生的假设。我们还将测试的假设，Bhlhe 40作为一个直接的转录调控基因控制自身反应性TH细胞的致病性，并确定这种转录调控所需的Bhlhe 40蛋白的结构特征。在目标2中，我们将使用Bhlhe 40-绿色荧光蛋白（GFP）报告小鼠来鉴定诱导T细胞中Bhlhe 40表达的信号，并测试Bhlhe 40表达决定自身反应性T细胞的致病性的假设。这些研究将有助于我们理解T细胞如何获得自身攻击性效应子功能，并将Bhlhe 40确定为治疗自身免疫性疾病的新治疗靶点。

DESCRIPTION (provided by applicant): CD4 T helper (TH) cells drive autoimmunity through their production of proinflammatory cytokines. The molecular determinants controlling the cytokine production and pathogenicity of autoreactive T cells remain unclear. In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), TH1, TH17 infiltrate the central nervous system (CNS). Remarkably, IFN-� and IL-17, the hallmark cytokines produced by TH1 and TH17 lineages, are not required for encephalitogenicity. Instead, the TH cell- cell-derived cytokine granulocyte-macrophage colony stimulating factor (GM-CSF, encoded by Csf2) plays a nonredundant role in mediating neuroinflammation. Immunosuppressive cytokines produced by autoreactive T cells, including IL-10, also influence T cell encephalitogenicity. We have discovered that mice deficient for the transcription factor Bhlhe40 are resistant to the induction of EAE. Bhlhe40-/- TH cells produce normal amounts of their hallmark cytokines, but produce decreased amounts of GM-CSF and increased amounts of IL-10. We will test the central hypothesis that Bhlhe40 is a required determinant for the pathogenicity of autoreactive T cells. In Aim 1, we will determine the mechanistic basis for Bhlhe40 function in neuroinflammation, testing the hypothesis that the nonencephalitogenicity of Bhlhe40-/- T cells is due to their cell-intrinsic IL-10 production. We will also test the hypothesi that Bhlhe40 acts as a direct transcriptional regulator of genes controlling autoreactive TH cell pathogenicity and determine the structural features of the Bhlhe40 protein required for this transcriptional regulation. In Aim 2, we will use Bhlhe40-green fluorescent protein (GFP) reporter mice to identify the signals that induce Bhlhe40 expression in T cells and test the hypothesis that Bhlhe40 expression determines the pathogenicity of autoreactive T cells. These studies will contribute to our understanding of how T cells acquire autoaggressive effector functions and could identify Bhlhe40 as a novel therapeutic target for the treatment of autoimmune disease.