Novel platelet functions for in T-cell helper cell responses

描述(由申请人提供)：我们建议通过趋化因子血小板因子4(PF4)在T辅助细胞稳态和慢性移植免疫反应中证明血小板的生物学和病理生理学作用。PF4因其在肝素诱导的血小板减少症(HIT)发病机制中的作用而广为人知，但尽管其血浆浓度较高，其生物学作用尚不清楚。我们新的令人兴奋的数据表明，在稳态和炎症条件下，PF4都是限制Th17分化所必需的。我们提出了一种假设，即血小板以PF4依赖的方式维持T-辅助平衡。这提出了血小板和CD4T细胞之间的串扰的新概念，并将血小板在免疫中的作用扩展到在维持T辅助平衡方面的获得性免疫作用。辅助性T细胞之所以得名，是因为它们的细胞因子影响许多其他细胞，如中性粒细胞和单核细胞数量的增加以及炎症性改变，而辅助性T细胞是B细胞抗体类别转换所必需的。因此，血小板对T辅助细胞数量和类型的调节暗示了血小板在免疫稳态中的重要作用。辅助性T细胞分为Th1、Th2、Th17和Tregs。我们的数据表明，在没有PF4的情况下，Th17细胞的数量在稳定状态下大大增加，在带血管的心脏移植的小鼠模型中，Th17细胞在移植后显著增加。我们还发现，在T细胞激活后，PF4的表达和产生被诱导，T细胞的PF4也限制了Th17的分化。因此，我们提出了以下目标：目标1：证明PF4是T辅助细胞分化的主要调节因子。目的：探讨PF4抑制Th17细胞分化的机制。我们的研究结果将影响炎症相关研究的许多领域，包括移植免疫反应。在降低移植急性排斥反应发生率方面取得了很大进展，但在预防慢性移植物血管病变方面进展不大。我们的结果表明，一种新的PF4介导的途径，调节CD4T细胞的移植反应。这些研究还将通过展示直接影响免疫发展的血小板和T细胞串扰的机制，影响炎症和免疫发展的许多其他领域。我们将在慢性心脏移植模型中使用基因修饰的血小板减少和PF4缺陷的小鼠来继续我们的新的和有影响力的研究。

DESCRIPTION (provided by applicant): We propose to demonstrate biologic and pathophysiologic roles for platelets via the chemokine platelet factor 4 (PF4) in T-helper cell homeostasis and chronic transplant immune responses. PF4 is best known for its role in the pathogenesis of heparin induced thrombocytopenia (HIT), but despite its high plasma concentration, biologic roles for PF4 are not well understood. Our new exciting data demonstrate that PF4 is needed to limit Th17 differentiation in both steady state and inflammatory conditions. We propose the hypothesis that platelets maintain T-helper balance in a PF4 dependent manner. This presents the novel concept of cross-talk between platelets and CD4+ T-cells and extends the role for platelets in immunity to an acquired immune role in the maintenance of T-helper balance. T-helper cells get their name from the fact that their cytokines influence many other cells such as increasing neutrophil and monocyte numbers and inflammatory profile and T-helper cells are necessary for B- cell antibody class switching. Therefore, platelet regulation of T-helper numbers and types implies a major role for platelets in immune homeostasis. T-helper cells are divided into Th1, Th2, Th17 and Tregs. Our data indicates that in the absence of PF4 there are greatly increased numbers of Th17 cells at steady state, and in a mouse model of vascularized cardiac transplant Th17 numbers increase greatly post-transplant. We have also discovered that PF4 expression and production is induced in T-cells post activation and T-cell PF4 also limits Th17 differentiation. As such we propose the following aims: Aim 1: To demonstrate that PF4 is a major mediator of T-helper differentiation. Aim 2: To demonstrate mechanisms for PF4 inhibition of Th17 differentiation. Results of our studies will impact many fields of inflammation related research, including transplant immune responses. Great progress has been made in reducing the incidence of acute transplant rejection, but less progress has been made in preventing chronic graft vasculopathy. Our results indicate a novel PF4 mediated pathway that regulates CD4+ T-cell responses to transplantation. These studies will also impact many other fields of inflammation and immune development by demonstrating a mechanism for platelet and T-cell cross-talk that directly affects immune development. We will use genetically modified thrombocytopenic and PF4 deficient mice in a chronic heart transplant model to pursue our novel and impactful studies.