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

风湿性关节炎（RA）是一种典型的自身免疫性疾病，其特征在于： 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 淋巴细胞在滑膜内聚集。最近，我们描述了一个群体PD-1hi CD 4 + 我们称之为T“外周辅助”（Tph）细胞的T细胞在RA中显著扩增 滑膜，并具有浸润发炎组织和促进B细胞增殖的能力 成熟和抗体产生（Rao等人，Nature，2017）。Tph细胞有几个共同的特点 与T滤泡辅助细胞（Tfh），已知的驱动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， 其促进B细胞存活，和CXCL 13，一种B细胞化学引诱物。然而，Tph细胞不同于 Tfh细胞表达趋化因子受体，归巢至炎症部位， 转录调节因子。 Tph细胞的发现对涉及以下疾病的临床意义 组织内自身抗体的产生，包括RA和SLE。选择性靶向Tph细胞 可能会中断自身抗体和下游炎症的局部产生， 瀑布然而，这样的靶向将需要精确表征的表型， 病理性Tph细胞和驱动Tph细胞的因素的更完整的理解 差异化和扩张。我们目前对Tph细胞的了解是有限的。 我们在目标1中提出使用以下方法定义Tph细胞的异质性和亚群： 无偏的单细胞转录组学，然后分离不同的亚群用于功能性 包括细胞因子产生的分析。在目标2中，我们深入了解了细胞因子信号传导 可能通过跟踪Tph细胞数量和功能的变化来改变体内Tph细胞， 目前用于RA的靶向治疗。最后，在目标3中，我们确定是什么驱动Tph细胞 分化和成熟。总之，这些研究将促进我们对 RA中新发现的Tph细胞的性质，并提供了解其 在RA免疫发病机制中的作用和潜在的治疗应用。

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.