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

描述（由申请人提供）：损伤和愈合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，但我们对该环境或其如何促进免疫调节知之甚少。 我们最近已经确定了透明质酸（HA）在Foxp3+调节性T细胞（Treg）（一种T细胞亚群）的功能和稳定性中的关键作用，透明质酸是损伤和愈合组织的细胞外基质（ECM）的组分。 对维持免疫耐受至关重要。HA对Treg的作用取决于其大小。 在愈合组织中发现的高分子量HA（HMW-HA）促进Treg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，以实现其活力和产生关键的免疫调节细胞因子IL-10。与此一致，CD44-/-小鼠对损伤有持续的炎症反应，Treg更少，产生的IL-10也更少。因此，HMW-HA作为组织完整性信号发挥作用，支持Treg在愈合组织中的作用。 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Toll样受体2（TLR2）配体; LMW-HA可以以与已知微生物TLR2配体抑制活性感染部位的Treg相同的方式负调节无菌炎症部位的Treg功能。 总之，我们的数据支持一个模型，即HA catalysts和信号转导通过CD44和TLR2连接炎症和Treg功能的无菌损伤部位。如果该模型是正确的，则可能通过支持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和共价连接HA链的其他HA结合分子（透明质酸粘蛋白）维持。这阻止了它们的降解并促进了与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，但其在自身免疫中的价值尚不清楚。 在这里，我们将阐明HMW-HA和LMW-HA控制Treg行为的机制，并确定HA完整性在体内Treg功能中的作用。 这些研究的预期成果是对损伤和愈合组织中免疫调节机制的有效认识，以及促进伤口愈合和预防自身免疫的创新的基于ECM的策略。 公共卫生相关性：拟议的研究将大大推进我们对损伤和愈合胰岛中免疫调节机制的理解，并将为预防自身免疫性糖尿病的创新策略打开大门。

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. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly advance our understanding of the mechanisms that govern immune regulation in injured and healing pancreatic islets and will open the doors to innovative strategies to prevent autoimmune diabetes.