Differential regulation of mast cell-mediated allergic responses by IL-10

项目总结 本项目的重点是IL-10调节和促进差异的机制 肥大细胞(MC)的增殖、异质性、活化和细胞功能 Ig E和非Ig E介导的食物抗原过敏反应的发展。 我们已经证明了免疫调节细胞因子IL-10在推动MC中的关键作用 食物过敏过程中的扩张、激活和细胞因子的产生。IL-10刺激的巨噬细胞展示 促增殖、IgE介导的被动过敏反应和TH2型的产生 细胞因子。这提示了IL-10在MCs的动态平衡和功能中的新作用。然而， IL-10促进MC活化的机制尚不十分清楚，尚不清楚 下定决心。此外，IL-10对MC的这些促炎作用是否延伸到 具体的MC谱系，本质上是全球性的，或者是上下文相关的，也有待研究。这 该项目结合了假设检验和有针对性的机械方法，以进一步探索 IL-10调节MC功能的机制。这些包括了解IL-10是否 不同地调节MC对不同抗原刺激的反应，评估其对 异质MC子集及其影响是否受源控制的确定 单元类型。长期的总体目标是：1)通过以下方式识别细胞内在和外在因素 IL-10促进或抑制不同的MC群体并调节其效应器功能 在2型炎症反应中；以及2)检查全身和功能局部组织 IL-10对MC扩增和激活的调节作用。目标1将阐明 IL-10促进IgE介导的粘膜MC对生理性食物抗原的应答 花生和鸡蛋变应原及其对非IgE介导的过敏反应途径的影响 致敏作用包括IL-33诱导的过敏反应。IL-10的影响是否也延伸到 将评估结缔组织MC以及两者的表型和转录图谱 将映射MC子集。目标2将评估细胞内源性和旁分泌IL-2的贡献。 10对MC的增殖和效应功能有影响。目标3将确定来源依赖的IL-1的影响 10，并确定TH2或非TH2来源的IL-10是否对MC功能有不同的调节作用。 鉴于已知的IL-10在不同T和MC中的多效性病理和调节作用- 包括抗寄生虫反应和过敏在内的介导性免疫反应，并考虑其 作为一种典型的免疫调节细胞因子，重要的是进一步确定其作用机制 IL-10的促炎作用及其促进而不是抑制的能力 MC依赖的反应。因此，这些研究不仅与NIAID的任务有关 但也可用于确定用于治疗干预的基于精度的方法。

PROJECT SUMMARY This project focuses on the mechanisms by which IL-10 differentially regulates and promotes mast cell (MC) hyperplasia, heterogeneity, activation and cellular functions during the development of IgE and non-IgE-mediated allergic responses to food antigens. We have demonstrated a key role for the immunomodulatory cytokine IL-10 in driving MC expansion, activation, and cytokine production during food allergy. IL-10-primed MCs exhibited enhanced proliferation, IgE-mediated passive anaphylaxis, and the production of TH2-type cytokines. This suggests a novel role for IL-10 in the homeostasis and function of MCs. However, the mechanisms by which IL-10 promotes MC activation are not very clear and remain to be determined. Furthermore, whether these proinflammatory effects of IL-10 on MCs extend to specific MC lineages, are global in nature, or context-dependent also remain to be examined. This project combines hypothesis testing and targeted mechanistic approaches to further probe the mechanisms by which IL-10 regulates MC functions. These include understanding whether IL-10 differentially regulates MC responses to distinct antigenic stimuli, assessment of its effects on heterogeneous MC subsets, and determination of whether its effects are controlled by the source cell type. The long-term overall goals are to: 1) identify cell-intrinsic and extrinsic factors by which IL-10 promotes or suppresses distinct MC populations and regulates their effector function during type 2 inflammatory responses; and 2) examine the systemic and functional local tissue consequences of regulation of MC expansion and activation by IL-10. Aim 1 will elucidate whether IL-10 promotes IgE-mediated mucosal MC responses to physiological food antigens such as peanut and egg allergen and examine its effects on non-IgE-mediated pathways of allergic sensitization including IL-33-induced anaphylaxis. Whether the effects of IL-10 also extend to connective tissue MCs will be assessed and the phenotypic and transcriptomic profiles of both MC subsets will be mapped. Aim 2 will assess the contributions of cell-intrinsic and paracrine IL- 10 to MC hyperplasia and effector function. Aim 3 will identify the effects of source-dependent IL- 10 and determine whether TH2 or non-TH2-derived IL-10 can differentially regulate MC function. Given the known pleiotropic pathologic and regulatory effects of IL-10 during various T and MC- mediated immune responses including anti-parasitic responses and allergy, and considering its status as a canonical immunoregulatory cytokine, it is important to further identify the mechanisms underlying the proinflammatory effects of IL-10 and its ability to promote rather than suppress MC-dependent responses. As such, these studies are not only relevant to the mission of NIAID but may also serve to identify precision-based approaches for therapeutic interventions.