Synthetic Ligands for Directing Immune Responses

摘要： 树突状细胞（Dendritic cells，DCs）位于先天免疫和适应性免疫的交界处。它们可以捕获 抗原，内化并降解它们，并将抗原衍生肽呈递给T细胞。的 在这些步骤中产生的信号导致形成T细胞应答的细胞因子的释放。 由于其作为关键抗原呈递细胞的作用，DC覆盖有能够 内化抗原-尤其是凝集素。DC表面的跨膜凝集素可以 结合并内化糖基化抗原，以影响DC信号传导和细胞因子， T细胞亚群的分化。因此，凝集素可以用来指导疫苗， 树突状细胞并定制它们引发的免疫反应。该项目的目标是 了解关键DC凝集素以利用这一潜力。 目标1着重于理解凝集素参与和信号传导的组合学。我们 假设能够结合Toll样受体和凝集素的聚糖将偏向DC信号传导 从而导致T细胞反应。我们建议确定具有这些性质的候选聚糖 通过评估DC凝集素（DC-SIGN、MGL、dectin-1、dectin-2）对微生物的选择性， 使用聚糖阵列分析聚糖。我们还将合成能够桥接DC凝集素和TLR的配体 直接检验双重参与的影响。在目标2中，我们将评估假设 DC凝集素起着机械传感器的作用。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方面不同。这些数据表明 DC-SIGN可以检测刚度的差异。病原体（例如，病毒、细菌、真菌） 比人类细胞更硬，因此抗原机械传感可能是区分外来细胞的一种手段。 从自我。了解抗原硬度如何影响凝集素和TLR信号传导， 调节免疫力的新策略。在目标3中，我们检查了对抗原的免疫应答， 体内靶向DC凝集素和TLR。拟议的实验利用了我们在以下方面的专业知识 化学生物学来测试关于信号通路和分子生物学的新假设。 这些机制是DCs如何塑造T细胞反应以及免疫力的基础。进展 旨在产生新的策略来招募免疫系统来治疗 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.