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Chemokine CXCL17 and Mucosal Immunosurveillance

趋化因子 CXCL17 和粘膜免疫监视

基本信息

批准号：
8391500
负责人：
Krishna Rajarathnam
金额：
$ 19.13万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391500
关键词：
Adopted Affinity Agonist Antigen-Presenting Cells Binding Biological Assay Breathing CX3CL1 gene CXCL12 gene Cell physiology Cells Characteristics Charge Chemotaxis Cysteine Dendritic Cells Dimerization Disulfides Eating Glycosaminoglycans Grant Heparin Homeostasis Human Immune Immune response Immunologic Monitoring Immunology In Vitro Inflammatory Knowledge Leukocytes Link Lung Mediating Modeling Mucous Membrane Mus Mutation N-terminal NMR Spectroscopy Organ Pattern Play Population Process Property Protein Chemistry Qualifying Receptor Activation Recruitment Activity Reporting Research Resolution Respiratory System Respiratory tract structure Role Sentinel Sequence Analysis Small Intestines Solutions Stomach Structure T-Lymphocyte Techniques Testing Tissues Virus Diseases arginyllysine base cell motility chemokine design disulfide bond experience in vivo insight migration monocyte novel pathogen receptor sedimentation equilibrium spatiotemporal three dimensional structure trafficking

项目摘要

DESCRIPTION (provided by applicant): CXCL17, a recently discovered chemokine, is constitutively expressed in mucosal tissues such as lung, stomach, and the small intestines. These organs are continuously exposed to a wide variety of pathogens via food intake and breathing, and so must be on high alert to mount a rapid and efficient immune response. CXCL17 could play an important role in this process, as it selectively recruits immature dendritic cells (DCs). These cells play a key role as immunological sentinels, and are professional antigen-presenting cells, and key regulators of T cell functions. Currently nothing is known about how CXCL17 mediates its in vivo functions. Characteristic features of chemokines are that they adopt the same three-dimensional structure, have four conserved cysteines that form two disulfide bonds, and bind glycosaminoglycans (GAGs). Both the disulfides are essential for receptor activation, and GAG binding is critical for directed migration of leukocytes. Most remarkably, sequence analysis reveals that CXCL17, has only three of the four conserved cysteines, and so may not adopt the typical chemokine structure; it also has a distinctly different distribution of positively charged residues, suggesting a novel GAG-binding mechanism. Another unusual feature of CXCL17 is that it is active only at high concentrations, and shows optimal activity at 100-1000x higher concentrations than is normally observed for most chemokines (?M vs. nM). As structure dictates function, we hypothesize that CXCL17-mediated recruitment of immature DCs from the vasculature to the tissues under steady-state conditions plays an important and non-redundant role in mucosal immunosurveillance. Our Specific Aims for this R21 grant are to: Aim 1. Characterize CXCL17-mediated recruitment of DC subtype(s) in vivo in a mouse lung, and recruitment of human DC subtype(s) in vitro using chemotaxis assays. Aim 2. Determine the CXCL17 solution structure and characterize its binding with GAG using NMR spectroscopy; and Aim 3. Determine whether CXCL17 can be converted to a more potent agonist by systematically deleting its N-terminal residues. PUBLIC HEALTH RELEVANCE: Organs such as the lung and stomach are continuously exposed to a wide variety of pathogens via food intake and breathing, and so must be on high alert for an efficient and quick immune response, a process during which specialized immune cells called dendritic cells (DCs) function as sentinels. We propose that CXCL17, a newly discovered chemokine, plays an important role in regulating DC function, and we further propose that CXCL17 is structurally unique, and that its structural properties are intimately linked to its ability to regulate DC function. Our planned studies on the structural and functional characterization of CXCL17 should provide critical insights into the immunosurveillance process in humans.

描述（由申请人提供）：CXCL 17是最近发现的趋化因子，在粘膜组织如肺、胃和小肠中组成型表达。这些器官通过食物摄入和呼吸持续暴露于各种病原体，因此必须保持高度警惕，以产生快速有效的免疫反应。CXCL 17可能在这个过程中发挥重要作用，因为它选择性地招募未成熟的树突状细胞（DC）。这些细胞作为免疫哨兵发挥关键作用，并且是专业的抗原呈递细胞和T细胞功能的关键调节剂。目前还不知道CXCL 17如何介导其体内功能。趋化因子的特征在于它们采用相同的三维结构，具有形成两个二硫键的四个保守半胱氨酸，并结合糖胺聚糖（GAG）。这两种二硫化物对受体活化是必不可少的，并且GAG结合对白细胞的定向迁移是至关重要的。最值得注意的是，序列分析显示，CXCL 17仅具有四个保守半胱氨酸中的三个，因此可能不采用典型的趋化因子结构;它还具有明显不同的趋化因子结构。带正电荷的残基的分布，表明一种新的GAG结合机制。CXCL 17的另一个不寻常的特征是它只在高浓度下才有活性，并且在比大多数趋化因子正常观察到的浓度高100- 1000倍的浓度下显示出最佳活性（？M对nM）。由于结构决定功能，我们假设CXCL 17介导的未成熟DC从血管系统募集到稳态条件下的组织中在粘膜免疫监视中起重要且非冗余的作用。我们的R21赠款的具体目标是：目标1。使用趋化性测定表征小鼠肺中CXCL 17介导的DC亚型体内募集和人DC亚型体外募集。目标二。确定CXCL 17溶液结构，并使用NMR光谱表征其与GAG的结合;和目的3.确定CXCL 17是否可以通过系统地删除其N-末端残基转化为更有效的激动剂。公共卫生相关性：肺和胃等器官通过食物摄入和呼吸持续暴露于各种病原体，因此必须高度警惕有效和快速的免疫反应，在此过程中，称为树突状细胞（DC）的专门免疫细胞起着哨兵的作用。我们提出，CXCL 17是一种新发现的趋化因子，在调节DC功能方面发挥着重要作用，我们进一步提出，CXCL 17在结构上是独特的，其结构特性与其调节DC功能的能力密切相关。我们计划的研究， CXCL 17的特征应该为人类的免疫监视过程提供重要的见解。