Synthetic Ligands for Directing Immune Responses

摘要： 树突状细胞(DC)位于天然免疫和获得性免疫的交界处。他们可以捕获 抗原，内化和降解它们，并将抗原衍生的多肽呈递给T细胞。这个 在这些步骤中产生的信号会导致细胞因子的释放，从而塑造T细胞的反应。 由于其作为关键的抗原提呈细胞的作用，树突状细胞被能够 内化抗原--尤其是凝集素。DC表面的跨膜凝集素可以 结合和内化糖基化抗原以影响DC信号和驱动的细胞因子 T细胞亚群的分化。因此，凝集素可以被利用来将疫苗引导到 树突状细胞，并定制它们所引发的免疫反应。这个项目的目标是 发展对关键DC凝集素的理解，以利用这一潜力。 目的1着重于了解凝集素参与和信号传递的组合。我们 假设可以结合Toll样受体和凝集素的多糖将偏向DC信号 因此T细胞会做出反应。我们建议确定具有这些性质的候选多糖 通过评估DC凝集素(DC-SIGN、MGL、Dectin-1、Dectin-2)对微生物的选择性 使用多聚糖阵列的多聚糖。我们还将合成能够连接DC凝集素和TLR的配体 直接考察双重参与的影响。在目标2中，我们将评估这一假设 DC凝集素起机械传感器的作用。我们对DC-SIGN的初步结果表明 颗粒抗原和可溶性抗原在运输上是不同的。这些数据表明 DC-SIGN可以检测刚度的差异。病原体(如病毒、细菌、真菌)有很多 比人类细胞更硬，所以抗原机械感应可能是区分异种 来自赛尔夫。了解抗原僵硬如何影响凝集素和TLR信号转导可能导致 调节免疫力的新策略。在目标3中，我们检查对下列抗原的免疫反应 体内靶向DC凝集素和TLRs。拟议的实验利用了我们在 化学生物学将测试有关信号通路和分子的新假说 树突状细胞如何塑造T细胞反应，从而影响免疫的机制。进展 建议的目的是产生新的策略，招募免疫系统进行治疗 人类疾病。

Abstract: Dendritic cells (DCs) reside at the interface of innate and adaptive immunity. They can capture antigens, internalize and degrade them, and present antigen-derived peptides to T cells. The signals generated in these steps result in the release of cytokines that shape T cell responses. Due to their roles as critical antigen-presenting cells, DCs are covered with receptors capable of internalizing antigens—especially lectins. The transmembrane lectins on the DC surface can bind and internalize glycosylated antigens to influence DC signaling and the cytokines that drive the differentiation of T cell subsets. As a result, lectins could be exploited to direct vaccines to dendritic cells and to tailor the immune responses they elicit. The goal of this project is to develop an understanding of key DC lectins to capitalize on this potential. Aim 1 focuses on understanding the combinatorics of lectin engagement and signaling. We hypothesize that glycans that can bind the toll-like receptors and lectins will bias DC signaling and therefore T cell responses. We propose to identify candidate glycans with these properties by assessing the selectivity of DC lectins (DC-SIGN, MGL, dectin-1, dectin-2) for microbial glycans using glycan arrays. We also will synthesize ligands that can bridge DC lectins and TLRs to examine the impact of dual engagement directly. In Aim 2, we shall evaluate the hypothesis that the DC lectins function as mechanosensors. Our preliminary results with DC-SIGN suggest that particulate antigens and soluble antigens differ in their trafficking. These data suggest that DC-SIGN can detect differences in stiffness. Pathogens (e.g., viruses, bacteria, fungi) are much stiffer than human cells, so antigen mechanosensing may be a means of distinguishing foreign from self. Understanding how antigen stiffness influences lectin and TLR signaling could lead to new strategies to modulate immunity. In Aim 3, we examine immune responses to antigens that target DC lectins and TLRs in vivo. The proposed experiments leverage our expertise in chemical biology to test novel hypotheses regarding the signaling pathways and molecular mechanisms that underlie how DCs shape T cell responses and, therefore, immunity. Progress on the proposed Aims is designed to yield new strategies to recruit the immune system to treat human disease.