ECM Costimulation of Immunoregulatory Pathways in Airway Inflammation

描述（由申请人提供）：在哮喘和过敏中可见的气道炎症的特征是免疫耐受的丧失。这种免疫失调归因于调节性t细胞的数量和功能减少，包括FoxP3+调节性t细胞（Treg）和产生IL-10的TR1。促进其数量和功能的策略将具有很大的治疗效益。Treg和TR1都需要通过IL-2R和TCR信号传导来诱导和维持。然而，IL-2的可用性受到严格调控，暴露于同源抗原通常是间歇性的。因此，在低IL-2和低同源抗原环境下支持调节性t细胞的机制对免疫稳态至关重要。PI已经确定了细胞外基质分子透明质酸（HA）及其受体CD44在促进调节性t细胞的数量和功能中的作用。CD44交联在低剂量抗原环境下促进Foxp3+ Treg的功能和维持。同样的线索也促进了传统t细胞前体对TR1的诱导。基于这一发现，鼻内注入低剂量抗原和HMW- HA在体内诱导抗原特异性TR1。这些反应是通过对IL-2R和TCR信号的协同作用介导的。由于高分子量HA （HMW-HA）而非低分子量HA （LMW-HA）能够交联CD44，因此组织完整性在这些作用中起决定性作用。

DESCRIPTION (provided by applicant): The loss of immune tolerance characterizes the airway inflammation seen in asthma and allergy. This immune dysregulation has been attributed to reduced numbers and function of regulatory T-cells, including FoxP3+ regulatory T-cells (Treg) and IL-10 producing TR1. Strategies to promote their numbers and function would have great therapeutic benefit. Both Treg and TR1 require signaling through the IL-2R and the TCR for their induction and maintenance. However, the availability of IL-2 is tightly regulated and exposure to cognate antigens is often intermittent. Mechanisms that support regulatory T-cells in settings of low IL-2 and low cognate antigen are therefore crucial to immune homeostasis. The PI has identified roles for the extracellular matrix molecule hyaluronan (HA) and its receptor CD44 in promoting the number and function of regulatory T-cells. CD44 crosslinking in the setting of low-dose antigen promotes the function and maintenance of Foxp3+ Treg. The same cues also promote the induction of TR1 from conventional T-cell precursors. Building on this finding, intra-nasal delivery of low dose antigen and HMW- HA was used to induce antigen-specific TR1 in vivo. These responses are mediated through synergistic effects on IL-2R and TCR signaling. Because high molecular weight HA (HMW-HA) but not low molecular weight HA (LMW-HA) is capable of crosslinking CD44, tissue integrity plays a decisive role in these effects. In Aims 1 and 2 the PI proposes to investigate the natural role of HMW-HA in Treg homeostasis. In Aim 3 the PI will evaluate whether TR1 induced using intra-nasal vaccination with a HMW-HA adjuvant can prevent inflammation in an antigen-specific mouse model of airway hypersensitivity. This is a novel and highly innovative approach to immune modulation with great potential for the prevention of asthma and allergy.