The control of allergic immune responses by follicular regulatory T cells

摘要 过敏性疾病和哮喘仍然是美国的主要健康问题，影响生活质量， 导致每年花费数十亿美元用于医疗保健和生产力损失。免疫球蛋白E (IgE)是过敏性疾病中涉及的速发型超敏反应的主要介质。以下 免疫系统对蠕虫寄生虫或过敏原的敏感性，随后的2型反应导致 T细胞产生IL-4和B细胞中IgE的类别转换。系统性IgE与肥大细胞结合， 通过FcεRI与嗜碱性粒细胞结合，随后用抗原激发，交联IgE结合受体 刺激过敏介质和细胞因子释放。CD 4 T细胞在发展中至关重要 免疫球蛋白E的反应。然而，T细胞如何调节IgE类别转换、产生和亲和力成熟并不清楚。 完全理解在过去二十年的大部分时间里，人们一直认为辅助性T细胞2（TH 2） 通过它们分泌IL-4的能力促进IgE应答。最近， T滤泡辅助细胞（TFH）为IgE反应增加了额外的复杂性。TFH细胞 定位于生发中心（GC）并控制其发育，生发中心是B细胞活化的主要位置， 分化、类别转换和抗体亲和力成熟。在一些过敏反应的小鼠模型中， TFH细胞是IgE转换所必需的，也是TH 2效应子形成所必需的。 细胞GC B细胞反应也受T滤泡调节（TFR）细胞调节，其表达Bcl 6和Bcl-2。 和Foxp 3定位于GC。在几种小鼠模型中，TFR细胞对抗体产生一系列影响， 从增强IG亲和力到抑制总体IG产生再到抑制伊加 切换TFR细胞还可以抑制TFH细胞的细胞因子产生。最近，我们发现TFR 细胞可以抑制小鼠中IgE的产生。然而，TFR细胞控制IgE的机制并不 TFR细胞控制过敏性免疫反应的总体程度还没有被完全理解。 表征了本申请的目的是确定TFR细胞对IgE产生的贡献， 亲和力成熟和TH 2效应T细胞反应，作为获得新见解的更大目标的一部分， 通过T细胞控制过敏性疾病。我们将分析过敏性疾病的这些方面使用两个 我们已经开发的条件突变小鼠模型，以及气道和胃肠道（GI）模型 过敏性炎症我们的总体假设是，TFR细胞通过以下方式抑制TH 2和IgE反应： 调节TFH细胞，但TFR细胞也增强IgE亲和力成熟。

ABSTRACT Allergic disease and asthma remain major health problems in the United States that impact quality of life and result in billions of dollars spent annually on healthcare and lost productivity . Immunoglobulin E (IgE) is the primary mediator of the immediate hypersensitivity involved in allergic disease . Following sensitization of the immune system to helminthic parasites or allergens, the ensuing type 2 response leads to IL-4 production from T cells and class switching to IgE in B cells. Systemic IgE binds to mast cells and basophils via the FcεRI, and upon subsequent challenge with antigen, crosslinked IgE-bound receptors stimulate release of anaphylactic mediators and cytokines. CD4 T cells are critical in the development of the IgE response. Yet, how T cells regulate IgE class switching, production and affinity maturation is not completely understood. The dogma for most of the past two decades was that T helper type 2 (TH2) cells promoted the IgE response through their ability to secrete IL-4. More recently, the identification of T follicular helper ( TFH) cells added an additional layer of complexity to the IgE response. TFH cells localize to, and control the development of, germinal centers (GCs), the major location of B cell activation, differentiation, class switching, and antibody affinity maturation. In some mouse models of allergic responses, TFH cells are absolutely required for IgE switching, and are also essential for the formation of TH2 effector cells. GC B cell responses are also regulated by T follicular regulatory (TFR) cells, which express both Bcl6 and Foxp3 and localize to the GC. In several mouse models, TFR cells have a range of effects on antibody production, from enhancing Ig affinity to suppressing overall Ig production to suppressing IgA switching. TFR cells can also suppress cytokine production by TFH cells. Recently, we have found that TFR cells can suppress the production of IgE in mice. However, the mechanism of IgE control by TFR cells is not understood, and the overall extent to which TFR cells control allergic immune responses has not been characterized. The goal of this application is to define the contributions of TFR cells to IgE production, IgE affinity maturation and TH2 effector T cell responses, as part of the larger goal of gaining new insights into the control of allergic diseases by T cells. We will analyze these aspects of allergic disease using two conditional mutant mouse models we have developed, and models for both airway and gastrointestinial (GI) allergic inflammation. Our overall hypothesis is that TFR cells repress TH2 and IgE responses by regulating TFH cells, but that TFR cells also enhance IgE affinity maturation.