The control of allergic immune responses by follicular regulatory T cells

滤泡调节性 T 细胞对过敏性免疫反应的控制

• 批准号: 10165474
• 负责人: Alexander L Dent
• 金额: $ 53.42万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165474
• 关键词: Aerosols; Affinity; Allergens; Allergic; Allergic Disease; Allergic inflammation; Allergy to peanuts; Anaphylaxis; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antigens; Asthma; B-Cell Activation; B-Lymphocytes; Basophils; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Data; Development; Effector Cell; Extrinsic asthma; FOXP3 gene; Generations; Goals; Health; Healthcare; Helper-Inducer T-Lymphocyte; High-Throughput Nucleotide Sequencing; Hypersensitivity; IgE; Immediate hypersensitivity; Immune response; Immune system; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Inflammatory Response; Interleukin-4; Lead; Location; Mediator of activation protein; Modeling; Mus; Mutant Strains Mice; Parasites; Pharmaceutical Preparations; Production; Productivity; Quality of life; Reaction; Regulation; Regulatory T-Lymphocyte; Role; Signal Pathway; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th2 Cells; Transcription Repressor; United States; allergic response; base; conditional mutant; crosslink; cytokine; defined contribution; effector T cell; experimental study; food allergen; insight; mast cell; mouse model; mutant mouse model; novel therapeutics; receptor binding; response

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.

抽象的 在美国，过敏性疾病和哮喘仍然是影响生活质量和的主要健康问题 导致每年数十亿美元用于医疗保健和生产力降低。免疫球蛋白E （IgE）是涉及过敏性疾病的直接超敏反应的主要介体。下列的 免疫系统对掌舵寄生虫或过敏原的敏化，随后的2型反应导致 IL-4从T细胞和类别切换到B细胞中的IgE的产生。全身IgE与肥大细胞和 通过FCεRI，随后挑战抗原，交联的IgE接收器，嗜碱性粒细胞 刺激过敏反应介质和细胞因子的释放。 CD4 T细胞对开发至关重要 但是，T细胞如何调节IgE类切换，生产和亲和力成熟不是 完全理解。在过去二十年的大部分时间里，教条是T辅助2型（Th2）细胞 通过秘密IL-4的能力促进了IgE响应。最近，识别 T滤泡辅助器（TFH）细胞为IgE响应增加了一层复杂性。 TFH细胞 本地化并控制生发中心（GCS）的发展，B细胞激活的主要位置， 分化，类开关和抗体亲和力成熟。在某些过敏反应的鼠标模型中 TFH细胞绝对需要IgE转换，对于形成Th2效应器也是必不可少的 细胞。 GC B细胞反应也受T卵泡调节（TFR）细胞的调节，该细胞表达这两个Bcl6 和foxp3并本地化为GC。在几种小鼠模型中，TFR细胞对抗体有一系列影响 生产，从增强IG亲和力到抑制总体IG产生到抑制IgA 交换。 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 细胞可以抑制小鼠的IgE产生。但是，TFR细胞控制IgE的机制不是 理解，以及TFR细胞控制过敏免疫反应的总体程度 特征。该应用的目的是定义TFR细胞对IgE产生的贡献 亲和力成熟和Th2效应子T细胞反应，作为获得新见解的更大目标的一部分 T细胞控制过敏性疾病。我们将使用两个 我们已经开发了有条件的突变小鼠模型，以及气道和胃肠道的模型（GI） 过敏性炎症。我们的总体假设是TFR细胞通过 调节TFH细胞，但TFR细胞也增强了IgE亲和力成熟。

项目成果

Germinal center B cells that acquire nuclear proteins are specifically suppressed by follicular regulatory T cells.

• DOI: 10.7554/elife.83908
• 发表时间: 2023-03-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Ke F;Benet ZL;Maz MP;Liu J;Dent AL;Kahlenberg JM;Grigorova IL
• 通讯作者: Grigorova IL

Follicular regulatory T cells inhibit the development of granzyme B-expressing follicular helper T cells.

• DOI: 10.1172/jci.insight.128076
• 发表时间: 2019-08
• 期刊: JCI insight
• 影响因子: 8
• 作者: Markus M. Xie;Shuyi Fang;Qiang Chen;Hong Liu;Jun Wan;A. Dent

Evidence that High-Affinity IgE Can Develop in the Germinal Center in the Absence of an IgG1-Switched Intermediate.

有证据表明，在没有 IgG1 转换中间体的情况下，生发中心可以形成高亲和力 IgE。

• DOI: 10.4049/jimmunol.2200521
• 发表时间: 2023
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Chen,Qiang;Liu,Hong;Luling,Noelle;Reinke,Julia;Dent,AlexanderL
• 通讯作者: Dent,AlexanderL

Unexpected Help: Follicular Regulatory T Cells in the Germinal Center.

• DOI: 10.3389/fimmu.2018.01536
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Xie MM;Dent AL
• 通讯作者: Dent AL