The Role of PI3K in the Maintenance and Function of T Follicular Regulatory Cells

项目摘要 调节性T细胞（Treg）是免疫调节所必需的CD 4 + FoxP 3 + T细胞群。 体内平衡和自发性自身免疫的预防。磷脂酰肌醇-3激酶 （PI 3 K）通路影响许多细胞类型的生长、增殖和存活， 最近表明，通过PTEN控制PI 3 K活性对于抑制功能和谱系至关重要， 稳定性的。在Treg区室中特异性缺乏PTEN的小鼠（Pten-ΔTreg）发展出一种新的免疫调节系统。 自身免疫性淋巴组织增生性疾病以及具有不稳定性的T细胞增多 FoxP 3表达。令人惊讶的是，年轻的未经操作的Pten-ΔTreg小鼠也出现了扩增的 生殖中心（GC）B细胞、T滤泡辅助（Tfh）细胞和T滤泡调节细胞群 (Tfr)细胞，伴随着大量的类别转换免疫球蛋白和自身抗体。 这表明，在最近描述的糖尿病中，PI 3 K活性的控制可能特别重要。 T滤泡调节（Tfr）细胞亚群，其调节GC活性和抗体产生。 本提案的目的将集中在了解PI 3 K信号通路如何影响 Tfr细胞在体内的维持和功能，可能揭示新的治疗靶点， 可用于调节抗体产生的控制。Pten-ΔTreg小鼠具有扩增的 Tfr细胞群体还发展出显著的体液异常，表明PI 3 K活性 改变体内Tfr细胞维持和抑制功能。在本提案的目标1中，我们将评估 Tfr细胞中的PI 3 K活性如何影响Tfr细胞的分化和基因表达谱。在 目的2将集中于Tfr细胞中PI 3 K活性如何影响两种细胞中GC活性的调节。 未操作和免疫的小鼠。了解控制体液免疫的调节机制 免疫应该转化为临床方法，这将是重要的，无论是在疾病的背景下， 治疗和预防性疫苗接种策略。更好地理解Tfr细胞 功能调节GC，以及如何利用PI 3 K等信号通路来控制其 功能增强，可以使我们更有效地治疗和/或预防抗体介导的 疾病，并改善疫苗接种策略。

Project Summary Regulatory T cells (Tregs) are a population of CD4+FoxP3+ T cells that are necessary for immune homeostasis and the prevention of spontaneous autoimmunity. The phosphtidylinositol-3 kinase (PI3K) pathway influences the growth, proliferation and survival of many cell types, and we have recently shown that control of PI3K activity by PTEN is critical for the suppressive function and lineage stability of Tregs. Mice that specifically lack PTEN in the Treg compartment (Pten-ΔTreg) develop an autoimmune lymphoproliferative disease as well as an expanded population of Tregs with unstable FoxP3 expression. Surprisingly, young unmanipulated Pten-ΔTreg mice also developed expanded populations of germinal center (GC) B cells, T follicular helper (Tfh) cells, and T follicular regulatory (Tfr) cells, accompanied by large amounts of class switched immunoglobulins and autoantibodies. This suggests that control of PI3K activity may be particularly important in the recently described subpopulation of T follicular regulatory (Tfr) cells, which regulate GC activity and antibody production. The aims in this proposal will focus on understanding the how the PI3K signaling pathway influences the maintenance and function of Tfr cells in vivo, potentially uncovering novel therapeutic targets that can be used to modulate control of antibody production. Pten-ΔTreg mice have an expanded population of Tfr cells yet develop significant humoral abnormalities, suggesting that PI3K activity alters Tfr cell maintenance and suppressive function in vivo. In Aim 1 of this proposal we will assess how PI3K activity in Tregs influences the differentiation and gene expression profiles of Tfr cells. In Aim 2 will focus on how PI3K activity in Tfr cells influences the regulation of GC activities in both unmanipulated and immunized mice. Knowledge of the regulatory mechanisms that control humoral immunity should translate into clinical approaches that will be important both in the context of disease treatment as well as prophylactic vaccination strategies. A better understanding of how Tfr cells function to regulate the GC, and how signaling pathways like PI3K can be utilized to control their function pharmacologically, may allow us to more efficiently treat and/or prevent antibody-mediated diseases as well as improve vaccination strategies.