Extracellular matrix and the function and stability of FoxP3+ regulatory T-cells

细胞外基质与 FoxP3 调节性 T 细胞的功能和稳定性

• 批准号: 8539603
• 负责人: Paul L Bollky
• 金额: $ 26.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539603
• 关键词: Active Sites; Autoimmune Diabetes; Autoimmunity; Behavior; Binding; CD44 gene; Catabolism; Cells; Characteristics; Complex; Cytometry; Data; Development; Diabetes Mellitus; Extracellular Matrix; Healed; Human; Hyaluronan; Immune; Immune Tolerance; Inbred NOD Mice; Infection; Inflammation; Inflammatory; Injury; Interleukin-10; Interleukin-2; Islets of Langerhans; Knowledge; Ligands; Link; Maintenance; Maps; Mediating; Modeling; Molecular Weight; Mus; Outcome Study; Phosphorylation; Play; Production; Regulation; Regulatory T-Lymphocyte; Resolution; Role; STAT5A gene; Sepsis; Signal Pathway; Signal Transduction; Site; Sterility; Streptozocin; T-Lymphocyte; T-Lymphocyte Subsets; Tissues; Toll-Like Receptor 2; Toxin; Work; Wound Healing; base; crosslink; cytokine; diabetic; healing; in vivo; injured; innovation; islet; microbial; mouse model; prevent; response to injury; versican

DESCRIPTION (provided by applicant): The inflammatory milieu in injured and healing islets is a decisive factor in the development of autoimmune diabetes and yet we know very little about this milieu or how it contributes to immune regulation. We have recently identified a pivotal role for hyaluronan (HA), a component of the extracellular matrix (ECM) of injured and healing tissues, in the function and stability of Foxp3+ regulatory T-cells (Treg), a T-cell subset critical to the maintenance of immune tolerance. The effect of HA on Treg depends on its size. High molecular weight HA (HMW-HA), found in healing tissues, promotes Treg survival and function. HMW-HA does this by crosslinking CD44 and substituting for IL-2 in the IL-2R signaling required by Treg for their viability and for production of the key immunoregulatory cytokine IL-10. Consistent with this, CD44-/- mice have unremitting inflammation in response to injury, fewer Treg, and make less IL-10. HMW-HA therefore functions as a tissue integrity signal that supports Treg in healing tissues. Low-molecular weight HA (LMW-HA), characteristic of chronically inflamed tissues, inhibits Treg function and suppresses production of IL-10. LMW-HA is a Toll like receptor 2 (TLR2) ligand; LMW-HA may negatively regulate Treg function at sites of sterile inflammation in the same way that microbial TLR2 ligands are known to inhibit Treg at sites of active infection. Together, our data support a model whereby HA catabolism and signaling through CD44 and TLR2 link inflammation to Treg function at sites of sterile injury. If this model is correct, it may be possible to enhance Treg function, promote wound healing and prevent autoimmunity by supporting HA integrity. In vivo HA integrity is maintained by TSG-6 and other HA-binding molecules (hyaladherins) that covalently link HA strands. This prevents their degradation and promotes interactions with CD44. TSG-6 has been used experimentally to treat sepsis and other forms of inflammation but its value in autoimmunity is unknown. Here, we will elucidate the mechanisms by which HMW-HA and LMW-HA govern Treg behavior and determine what role HA integrity plays in Treg function in vivo using mouse models of autoimmune diabetes. The expected outcomes of these studies are a working knowledge of the mechanisms that govern immune regulation in injured and healing tissues and innovative, ECM-based strategies to promote wound healing and prevent autoimmunity.

描述（由申请人提供）：受伤和正在愈合的胰岛中的炎症环境是自身免疫性糖尿病发展的决定性因素，但我们对这种环境或其如何促进免疫调节知之甚少。 我们最近发现透明质酸 (HA)（受伤和愈合组织的细胞外基质 (ECM) 的一种成分）在 Foxp3+ 调节性 T 细胞 (Treg)（一种 T 细胞亚群）的功能和稳定性中发挥着关键作用 对维持免疫耐受至关重要。 HA 对 Treg 的影响取决于其大小。 在愈合组织中发现的高分子量 HA (HMW-HA) 可促进 Treg 的存活和功能。 HMW-HA 通过交联 CD44 并取代 Treg 所需的 IL-2R 信号传导中的 IL-2 来实现这一点，以维持其活力并产生关键的免疫调节细胞因子 IL-10。与此一致的是，CD44-/- 小鼠对损伤有持续的炎症反应，Treg 细胞较少，IL-10 产生较少。因此，HMW-HA 作为组织完整性信号，支持 Treg 细胞愈合组织。 低分子量 HA (LMW-HA) 是慢性炎症组织的特征，可抑制 Treg 功能并抑制 IL-10 的产生。 LMW-HA 是一种 Toll 样受体 2 (TLR2) 配体； LMW-HA 可能对无菌性炎症部位的 Treg 功能产生负调节，就像微生物 TLR2 配体在活动性感染部位抑制 Treg 的作用一样。 总之，我们的数据支持一个模型，其中 HA 分解代谢和通过 CD44 和 TLR2 的信号传导将炎症与无菌性损伤部位的 Treg 功能联系起来。如果这个模型正确，就有可能通过支持 HA 完整性来增强 Treg 功能、促进伤口愈合并预防自身免疫。 体内 HA 完整性由 TSG-6 和其他共价连接 HA 链的 HA 结合分子（玻璃粘着素）维持。这可以防止它们降解并促进与 CD44 的相互作用。 TSG-6 已在实验中用于治疗脓毒症和其他形式的炎症，但其在自身免疫方面的价值尚不清楚。 在这里，我们将利用自身免疫糖尿病小鼠模型阐明 HMW-HA 和 LMW-HA 控制 Treg 行为的机制，并确定 HA 完整性在体内 Treg 功能中发挥的作用。 这些研究的预期结果是了解受伤和愈合组织中免疫调节的机制，以及基于 ECM 的创新策略，以促进伤口愈合和预防自身免疫。