Newly Identified T Peripheral Helper (Tph) Cells in Rheumatoid Arthritis

新发现的类风湿关节炎外周辅助 T (Tph) 细胞

• 批准号: 10197753
• 负责人: Michael B. Brenner
• 金额: $ 50.03万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197753
• 关键词: Affect; Anti-Tumor Necrosis Factor Therapy; Antibodies; Antibody Formation; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; BLR1 gene; Biological Response Modifier Therapy; CD4 Positive T Lymphocytes; CRISPR/Cas technology; CXCL13 gene; Cell Count; Cell Differentiation process; Cell Maturation; Cell Survival; Cell physiology; Cells; Characteristics; Chemotactic Factors; Chronic; Clinical; Collaborations; Cytokine Signaling; Data; Disease; Frequencies; Genetic Transcription; Helper-Inducer T-Lymphocyte; Heterogeneity; Homing; Human; Hyperplasia; In Vitro; Inflammation; Inflammatory; Interferon Type I; Interferons; Interruption; Joints; Knowledge; Leukocytes; Lymphocyte; Lymphoid; Lymphoid Follicle; Lymphoid Tissue; MHC Class II Genes; Maintenance; Mediating; Nature; PRTN3 gene; Pain; Pathologic; Pathway interactions; Patients; Peripheral; Phenotype; Play; Population; Production; Resolution; Rheumatoid Arthritis; Rheumatoid Factor; Role; STAT3 gene; Signal Transduction; Site; Sjogren' s Syndrome; Structure; Sushi Domain; Swelling; Synovial Fluid; Synovial Membrane; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Tissues; Work; arthritis therapy; autoreactive T cell; chemokine receptor; citrullinated protein; cohort; cytokine; exhaust; immunopathology; in vivo; insight; joint inflammation; joint injury; programmed cell death protein 1; receptor; response; rituximab; seropositive; targeted treatment; transcriptome sequencing; transcriptomics

Rheumatoid arthritis (RA) is a prototypical autoimmune disease characterized by activation of autoreactive T cells and B cells, production of autoantibodies, and accumulation of lymphocyte aggregates within the synovium. Recently, we described a population PD-1hi CD4+ T cells that we called T `peripheral helper' (Tph) cells that is markedly expanded within RA synovium and possesses the capacity to infiltrate inflamed tissues and promote B cell maturation and antibody production (Rao et al., Nature, 2017). Tph cells share several features with T follicular helper (Tfh) cells, the principal T cell subset known to drive B cell maturation in secondary lymphoid tissues. Like Tfh cells, synovial Tph cells express high levels of IL-21, which promotes B cell survival, and CXCL13, a B cell chemoattractant. Yet, Tph cells differ from Tfh cells in expression of chemokine receptors for homing to inflammatory sites and in transcriptional regulators. The discovery of Tph cells has clinical implications for diseases that involve autoantibody production within tissues, including RA and SLE. Selective targeting of Tph cells could potentially interrupt local production of autoantibodies and downstream inflammatory cascades. However, such targeting will require a precise characterization of the phenotype of pathologic Tph cells and a more complete understanding of the factors that drive Tph cell differentiation and expansion. Our current knowledge of Tph cells is limited. We propose in Aim 1 to define the heterogeneity and subpopulations of Tph cells using unbiased single cell transcriptomics followed by isolation of distinct subpopulations for functional analysis including cytokine production. In Aim 2, we gain insight into how cytokine signaling may alter Tph cells in vivo by tracking changes in Tph cell numbers and function in response to currently used targeted therapies for RA. Finally, in Aim 3 we determine what drives Tph cell differentiation and maturation. Together, these studies will advance our knowledge of the nature of newly identified Tph cells in RA and provide information critical to understanding their role in the immunopathogenesis of RA and potential applications for therapy.

类风湿性关节炎（RA）是一种典型的自身免疫性疾病，其特征是 自身反应性 T 细胞和 B 细胞的激活、自身抗体的产生以及自身抗体的积累 淋巴细胞聚集在滑膜内。最近，我们描述了一个群体 PD-1hi CD4+ T 细胞，我们称为 T“外周辅助细胞”(Tph) 细胞，在 RA 内显着扩增 滑膜并具有浸润发炎组织和促进 B 细胞的能力 成熟和抗体产生（Rao 等人，Nature，2017）。 Tph 细胞有几个共同特征 滤泡辅助 T (Tfh) 细胞是已知驱动 B 细胞成熟的主要 T 细胞亚群 次级淋巴组织。与 Tfh 细胞一样，滑膜 Tph 细胞表达高水平的 IL-21， 促进 B 细胞存活，以及 CXCL13（一种 B 细胞趋化剂）。然而，Tph 细胞不同于 Tfh 细胞表达趋化因子受体以归巢至炎症部位并在 转录调节因子。 Tph 细胞的发现对涉及以下疾病的临床意义 组织内产生自身抗体，包括 RA 和 SLE。 Tph 细胞的选择性靶向 可能会中断自身抗体和下游炎症的局部产生 级联。然而，这种靶向需要对表型进行精确表征。 病理性 Tph 细胞以及对驱动 Tph 细胞的因素有更全面的了解 分化和扩张。我们目前对 Tph 细胞的了解有限。 我们在目标 1 中建议使用以下方法定义 Tph 细胞的异质性和亚群： 无偏见的单细胞转录组学，然后分离不同的亚群以进行功能分析 分析，包括细胞因子的产生。在目标 2 中，我们深入了解细胞因子信号传导如何 可能通过跟踪 Tph 细胞数量和功能的变化来改变体内的 Tph 细胞 目前RA的靶向治疗。最后，在目标 3 中，我们确定驱动 Tph 细胞的因素 分化和成熟。总之，这些研究将增进我们对 RA 中新鉴定的 Tph 细胞的性质，并提供对于了解其细胞至关重要的信息 在 RA 免疫发病机制中的作用及其潜在的治疗应用。