Control of Treg Homeostasis and Function by the Lipid Phosphatase PTEN

脂质磷酸酶 PTEN 对 Treg 稳态和功能的控制

基本信息

批准号：
8722954
负责人：
Laurence A Turka
金额：
$ 19.83万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8722954
关键词：
Affect Age Alleles Allografting Animals Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity Behavior Biochemical Breeding CD28 gene CD8B1 gene Cancer Cell Growth Cell Lineage Cells Chromosomes, Human, Pair 10 Cytokine Receptors Data Defect Development Down-Regulation Drug Targeting Experimental Autoimmune Encephalomyelitis Exposure to Functional disorder Genes Goals Graft Rejection Grant Homeostasis Homing Human IL2RA gene IL7R gene Immune Immune Tolerance Immune system In Vitro Individual Infection Inflammatory Interleukin-2 Knock-in Mouse Laboratories Lead Link Lipids Lymphocyte Lymphoproliferative Disorders Maps Modeling Mus Neuropilin-1 Non-Malignant Organ PTEN gene Pathway interactions Phenotype Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Population Receptor Signaling Regulatory T-Lymphocyte Research Role SELL gene STAT5A gene Serum Signal Pathway Signal Transduction Surface T cell response T-Cell Activation T-Lymphocyte Teleconferences Therapeutic Time Transgenic Animals Transplantation Transplanted tissue Work cytokine in vivo insight interest meetings migration prevent programs public health relevance receptor receptor expression research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Our laboratories have a long-standing interest in immune tolerance in transplantation and autoimmunity, with a particular focus on regulatory T cells (Tregs). The primary population of Tregs in humans and mice is defined by expression of the X-linked transcription factor Foxp3. While these cells are required for normal immune homeostasis increasing data suggests that this lineage of cells may be unstable (e.g., as a result for example of inadequate IL-2, TCR and CD28 stimulation, or due to exposure to inflammatory cytokines), meaning that Tregs can revert/convert to effector T cells and thus contribute to loss of tolerance to self or to transplanted allografts. One of the key pathways controlling lymphocyte lineage specification and responsiveness is the phosphoinositide 3-kinase (PI3K) pathway, which can be activated via multiple surface receptors, including, most prominently, CD28 and the IL-2R. While this pathway is essential for conventional T cell responses, it may have limited, if any, function in Tregs. In fact, over activation of the PI3K pathway dramatically inhibits Treg development, while the STAT5 pathway, which is also activated through the IL-2R, strongly promotes Tregs. The primary regulator of PI3K activity in T cells is the lipid phosphatase PTEN (phosphatase and tensin homolog on chromosome 10). The goal of this proposal is to determine how PTEN in Tregs controls Treg homeostasis, the integration of PI3K and STAT5 signals, and whether drug targeting of the PI3K pathway can stabilize Tregs. To accomplish this, we created mice with PTEN deleted specifically in Tregs by breeding mice with a PTENfl/fl allele with Foxp3-YFP-Cre knock-in or BAC transgenic animals to generate PTEN-¿Treg mice. Surprisingly, although these mice have elevated numbers of Tregs, a high proportion of those cells are CD25- and CD62Llo, and the animals develop a severe polyclonal lymphoproliferative disorder. This has led us to formulate the hypothesis that PTEN loss disrupts Treg homeostasis due to reduced cytokine receptor expression, altered migration and apparent loss of regulatory capacity. The goal of this grant is to determine how PTEN in Tregs controls Treg homeostasis, the integration of PI3K and STAT5 signals, and whether drug targeting of the PI3K pathway can stabilize Tregs. To do so, we have two aims. In Aim #1, employing Treg fate mapping mice with Treg specific deletion of PTEN, we will examine the effects of loss of PTEN on natural and adaptive Treg stability and function, both under homeostatic conditions and in a model autoimmune disease. In Aim #2, we will dissect the signals downstream of CD25, PI3K and STAT5 to determine which are responsible for the Treg phenotypic and functional changes we have observed. Our studies will yield new insights into Treg signaling pathways and provide potential therapeutic strategies to enhance immune tolerance.

描述（由应用提供）：我们的实验室对移植和自身免疫性的免疫耐受性具有长期的兴趣，特别关注调节T细胞（TREG）。人类和小鼠中Treg的主要人口是由X连锁转录因子Foxp3的表达定义的。虽然这些细胞是正常的免疫抑制性增加数据所必需的，这表明细胞的这种谱系可能不稳定（例如，例如，例如，IL-2，TCR和CD28模拟不足，或者是由于暴露于炎症细胞因子而导致的），这意味着TREG可以恢复/转化为效应T细胞，从而使耐受性的损失损失，从而使人自我损失。控制淋巴细胞谱系规范和反应性的关键途径之一是磷酸肌醇3-激酶（PI3K）途径，可以通过多个表面受体激活，其中包括最突出的CD28和IL-2R。尽管该途径对于常规T细胞响应至关重要，但它在Treg中的功能可能有限（如果有）。实际上，PI3K途径的激活极大地抑制了Treg的发展，而STAT5途径也通过IL-2R激活，强烈促进了Treg。 T细胞中PI3K活性的主要调节剂是脂质磷酸酶PTEN（染色体10上的磷酸酶和Tensin同源物）。该提案的目的是确定Tregs中的PTEN如何控制Treg稳态，PI3K和STAT5信号的整合以及PI3K途径的药物靶向是否可以稳定Tregs。为此，我们通过用PTENFL/FL等位基因用Foxp3-YFP-Cre敲入或BAC转基因动物繁殖小鼠，创建了在Treg中专门删除的PTEN小鼠，以产生PTEN-€treg小鼠。令人惊讶的是，尽管这些小鼠的Treg数量升高，但其中很大的细胞是CD25-和CD62LLO，并且动物患有严重的多克隆淋巴增生障碍。这使我们提出了这样的假设，即由于细胞因子受体表达降低，迁移改变和监管能力的明显丧失，PTEN损失破坏了Treg稳态。该赠款的目的是确定Tregs中的PTEN如何控制Treg稳态，PI3K和STAT5信号的整合以及PI3K途径的药物靶向是否可以稳定Tregs。为此，我们有两个目标。在AIM＃1中，采用Treg脂肪映射小鼠的PTEN特异性缺失，我们将研究PTEN丢失对自然和适应性Treg稳定性和功能的影响，包括在体内稳态条件下以及模型自动免疫性疾病。在AIM＃2中，我们将剖析CD25，PI3K和STAT5下游的信号，以确定我们观察到的Treg表型和功能变化的原因。我们的研究将为Treg信号通路提供新的见解，并提供潜在的治疗策略来增强免疫耐受性。