Regulation of T cell exit from non-lymphoid tissues

T 细胞从非淋巴组织退出的调节

• 批准号: 10660163
• 负责人: Susan Ruth Schwab
• 金额: $ 52.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660163
• 关键词: Address; Animals; CXCR4 gene; Cell physiology; Cells; Chronic; Circulation; Communities; Cues; Disease; Disease model; Endothelium; Enterobacteria phage P1 Cre recombinase; Flow Cytometry; Gene Expression; Gene Targeting; Genes; Grant; Height; Image; Immune; Immune response; Immunology; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Infiltrate; Injections; Inorganic Phosphate Transporter; Left; Light; Lipids; Location; Lymph; Lymphatic; Memory; Modeling; Mus; Organ; Oxazolone; Periodicals; Phase; Play; Regulation; Reporter; Reporting; Reproducibility; Role; Shapes; Signal Transduction; Site; Skin; Specificity; Sphingosine-1-Phosphate Receptor; Staphylococcus aureus; Staphylococcus aureus infection; T cell regulation; T cell response; T-Cell Development; T-Lymphocyte; Testing; Thymus Gland; Time; Tissues; Vaccine Design; Visualization; cell motility; cell type; clinically relevant; draining lymph node; exhaustion; genetic manipulation; inducible Cre; inhibitor; interest; irritation; lymph nodes; monocyte; mouse model; novel; prevent; receptor; response; single-cell RNA sequencing; sphingosine 1-phosphate; tissue resident memory T cell; tool; vaccine strategy

Project Abstract T cell exit from a site of inflammation plays key roles in the immune response. At the effector phase of an immune response, T cell exit has been reported to limit tissue inflammation. By contrast, periodic T cell exit from a site of chronic inflammation might prevent T cell exhaustion and sustain the immune response. As memory develops, T cell exit from a site of inflammation limits the formation of resident memory T cells. Whether the T cells that have exited the tissue become a unique form of circulating memory cells is unknown. Overall, while the function of resident memory T cells remaining at a site of inflammation is increasingly well understood, the function of cells that have left a site of inflammation remains unclear. One cue that regulates T cell exit from a site of inflammation is the signaling lipid sphingosine 1- phosphate (S1P). Generally, S1P levels are high in lymph compared to tissues, and S1P guides immune cells out of tissues into lymphatics. This paradigm has been well-established for T cell exit from lymph nodes into efferent lymphatics, and some studies indicate that it holds for T cell exit from non-lymphoid tissues into lymph. Yet we do not understand how S1P gradients are shaped in non-lymphoid tissues during an immune response, or how S1P might interact with other cues that might guide T cell exit from non-lymphoid tissues. A key barrier to answering these questions is our inability to manipulate gene expression with spatial specificity. Thus, we cannot permanently mark T cells at a site of inflammation and follow them through a memory response. Similarly, we cannot disrupt genes that regulate chemotactic cues only at a site of inflammation, avoiding confounding effects on T cell development and differentiation in the thymus and lymph nodes. Conditional gene targeting allows manipulation of gene expression in a cell-type specific and, in some models, inducible manner. However, all murine targeting approaches are currently limited to altering gene expression in entire lineages, and it is not possible to institute permanent changes in cells within a specific location in the animal. To address this problem, we have generated a mouse expressing a light-inducible Cre recombinase (LI- Cre), which allows us to alter gene expression in cells of interest in a location-specific and time-specific manner using blue light. In this grant, we will take advantage of this novel mouse model to answer key questions about the regulation and function of T cell exit from inflamed skin. We will address how S1P receptor 1 cooperates with other candidate exit receptors in two well-defined models of disease, ask how S1P gradients change in the skin during the course of disease, and track the fate of T cells that have exited the skin in the memory phase and in recall responses.

项目摘要 T细胞从炎症部位退出在免疫应答中起关键作用。在效应阶段， 作为免疫应答，T细胞的退出已被报道限制组织炎症。相比之下，周期性T细胞退出 从慢性炎症的部位提取的DNA可能会阻止T细胞耗尽并维持免疫反应。诸如存储器 当T细胞从炎症部位退出时，限制了驻留记忆T细胞的形成。如果T 已经离开组织的细胞变成循环记忆细胞的独特形式是未知的。总体而言，虽然 在炎症部位保留的常驻记忆T细胞的功能越来越好地理解， 留下炎症部位的细胞的功能仍不清楚。 调节T细胞从炎症部位退出的一个线索是信号脂质鞘氨醇1- 磷酸盐（S1 P）。通常，与组织相比，淋巴中的S1 P水平较高，并且S1 P引导免疫细胞 从组织中分离出来变成了细胞。对于T细胞从淋巴结退出进入淋巴结，这种范例已经得到了很好的建立。 一些研究表明，它适用于T细胞从非淋巴组织进入淋巴。 然而，我们不了解S1 P梯度在免疫应答期间在非淋巴组织中是如何形成的， 或者S1 P如何与其他可能引导T细胞从非淋巴组织中退出的信号相互作用。 回答这些问题的一个关键障碍是我们无法用空间调控基因表达。 的特异性因此，我们不能在炎症部位永久标记T细胞，并通过记忆跟踪它们。 反应同样，我们不能破坏只在炎症部位调节趋化因子的基因， 避免了对胸腺和淋巴结中T细胞发育和分化的混杂影响。 条件基因靶向允许在细胞类型特异性中操纵基因表达，并且在一些模型中， 诱导的方式。然而，目前所有鼠靶向方法都仅限于改变基因表达， 整个谱系，并且不可能在细胞中的特定位置内建立永久性变化。 动物为了解决这个问题，我们已经产生了表达光诱导型Cre重组酶（L1-Cre）的小鼠。 Cre），这使我们能够以位置特异性和时间特异性的方式改变感兴趣细胞中的基因表达 使用蓝光。 在这项资助中，我们将利用这种新颖的小鼠模型来回答关于 调节和功能的T细胞退出发炎的皮肤。我们将讨论S1 P受体1如何与 在两种明确定义的疾病模型中，其他候选出口受体询问皮肤中S1 P梯度如何变化 在疾病过程中，并追踪在记忆阶段和后期离开皮肤的T细胞的命运 回忆回答。