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

类风湿关节炎(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，自身抗体的产生和聚集 淋巴细胞聚集在滑膜内。最近，我们描述了一种PD-1HIVCD T细胞，我们称之为T‘外周辅助’(TPH)细胞，在RA内显著扩张 滑膜，并具有渗透炎症组织和促进B细胞的能力 成熟和抗体产生(Rao等人，《自然》，2017)。TPH细胞有几个共同的特征 在T滤泡辅助细胞(TFH)中，已知的推动B细胞成熟的主要T细胞亚群 次级淋巴组织。和TFH细胞一样，滑膜TPH细胞也表达高水平的IL-21， 它可以促进B细胞存活，CXCL13是一种B细胞趋化物质。然而，TPH细胞与 TFH细胞在趋化因子受体表达中的作用 转录调控因子。 TPH细胞的发现对以下疾病具有临床意义 自身抗体在组织内产生，包括类风湿性关节炎和系统性红斑狼疮。TPH细胞的选择性靶向研究 可能会潜在地干扰局部自身抗体的产生和下游炎症 瀑布。然而，这样的靶向将需要精确的表型特征 病理的TPH细胞和对驱动TPH细胞的因素的更全面的了解 差异化和扩大化。我们目前对TPH细胞的了解是有限的。 在目标1中，我们建议使用以下方法定义TPH细胞的异质性和亚群 无偏向单细胞转录分离后分离出不同的功能亚群 分析包括细胞因子的产生。在目标2中，我们深入了解了细胞因子信号转导 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 目前用于类风湿关节炎的靶向治疗。最后，在目标3中，我们确定了是什么驱动了TPH细胞 分化和成熟。总而言之，这些研究将促进我们对 新发现的类风湿关节炎患者的TPH细胞的性质，并提供对理解其 在类风湿关节炎免疫发病机制中的作用及潜在的治疗应用。

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.