Functions of Hopx in immune tolerance in a model of Multiple Sclerosis

描述(由申请人提供)：免疫耐受性的崩溃和促炎淋巴细胞的产生会导致自身免疫性疾病，包括多发性硬化症(MS)。树突状细胞(DC)诱导免疫和耐受，是MS新的免疫治疗靶点。在自身免疫性实验性急性脑脊髓炎(EAE)中，T细胞耐受途径包括自身反应性T细胞的缺失、无能和免疫抑制被证明对疾病具有保护作用。然而，DC介导耐受的具体机制尚不清楚。我们最近发现，只有同源结构域的蛋白(Hopx)可以引导树突状细胞(DC)诱导的Treg细胞免疫无反应。Hopx是一种转录辅助因子，通过与包括血清反应因子(SRF)在内的其他蛋白质相互作用，以不同的方式调节c-jun/c-fos等基因的表达。我们的最新发现表明，DC通过密切相关的途径介导耐受，包括早期诱导T细胞对EAE的激活无反应，诱导Hopx+/Foxp3neg细胞的表达，并可将Hopx+/Foxp3neg细胞转化为Hopx+/Foxp3+外周(P)Treg细胞。这些胸腺外诱导的pTreg细胞然后介导持久的耐受，以阻断自身免疫性EAE。在pTreg细胞中表达的Hopx通过抑制IL-2的表达来维持这些调节细胞的功能。我们的 结果确立了Hopx作为DC诱导耐受以避免自身免疫所需的第一个特征性转录辅助因子，为DC介导的免疫耐受开辟了一个新的研究领域。我们的长期目标是建立一种新的、全面的耐受Hopx功能模型。我们将通过阐明包括IL-2在内的特定Hopx分子靶点在Aim 1中的功能来揭示Hopx在pTreg细胞中的分子通路。我们将在Aim 2中了解Hopx在耐受中的表达调控。在Aim 3中，我们将确定Hopx在不同类型DC介导的多种耐受机制中的作用。所提出的实验结果可能为更选择性和有效地治疗MS和其他类型的自身免疫性疾病奠定基础。

DESCRIPTION (provided by applicant): A breakdown of immune tolerance and the generation of pro-inflammatory lymphocytes cause autoimmune diseases, including Multiple Sclerosis (MS). Dendritic cells (DCs) induce immunity and tolerance and therefore represent a promising target for new immune-therapies of MS. Pathways of T cell tolerance that include deletion, anergy, and immune-suppression of autoreactive T cells were shown to confer protection from disease in autoimmune Experimental Acute Encephalomyelitis (EAE), a mouse model of MS. However, the specific mechanisms of tolerance mediated by DCs remain unclear. We recently discovered that Homeodomain Only Protein (Hopx) directs Treg cell-mediated immune unresponsiveness induced by DCs. Hopx is a transcription co-factor that differently regulates expression of c- jun/c-fos and other genes through its interactions with other proteins including Serum Response Factor (SRF). Our most recent findings reveal that DCs mediate tolerance through intimately linked pathways involving the early induction of tolerance in T cells that become unresponsive to activation in EAE, induce expression of Hopx and Hopx+/Foxp3neg cells can convert into Hopx+/Foxp3+ peripheral (p)Treg cells. These extrathymically- induced pTreg cells then mediate long-lasting tolerance to block autoimmune EAE. Hopx expressed in pTreg cells maintains the functions of these regulatory cells by inhibiting their expression of IL-2. Our results firmly establish Hopx as the first characterized transcription co-factor specifically required for DC- induced tolerance to avert autoimmunity, and they open a new area of investigation in immune tolerance mediated by DCs. Our long-term goals are to establish a novel and comprehensive model of Hopx functions in tolerance. We will reveal molecular pathways of Hopx in pTreg cells by clarifying functions of specific Hopx molecular targets including IL-2 in Aim 1. We will discern regulation of Hopx expression in tolerance in Aim 2. We will define the role for Hopx in diverse mechanisms of tolerance mediated by various types of DCs in Aim 3. The results of the proposed experiments may become a foundation of more selective and efficient therapies for MS as well as other types of autoimmune diseases.