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作用。PF4以其在肝素诱导的血小板减少症（HIT）发病机制中的作用而闻名，但尽管其血浆浓度很高，但PF4的生物学作用尚不清楚。我们激动人心的新数据表明，在稳态和炎症条件下，都需要PF4来限制Th17的分化。我们提出血小板以依赖PF4的方式维持t辅助平衡的假设。这提出了血小板和CD4+ t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维持t辅助平衡的获得性免疫作用。t辅助细胞之所以得名，是因为它们的细胞因子影响许多其他细胞，如增加中性粒细胞和单核细胞的数量和炎症谱，t辅助细胞是B细胞抗体类别转换所必需的。因此，血小板对辅助性t细胞数量和类型的调节意味着血小板在免疫稳态中起着重要作用。辅助t细胞分为Th1、Th2、Th17和treg。我们的数据表明，在缺乏PF4的情况下，Th17细胞的数量在稳态下大大增加，并且在血管化心脏移植小鼠模型中，Th17细胞的数量在移植后大大增加。我们还发现，激活后的t细胞会诱导PF4的表达和产生，并且t细胞的PF4也会限制Th17的分化。因此，我们提出以下目标：目的1：证明PF4是t辅助分化的主要中介。目的2：阐明PF4抑制Th17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。在降低急性移植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较少。我们的研究结果表明，一种新的PF4介导的途径可以调节CD4+ t细胞对移植的反应。这些研究还将通过证明血小板和t细胞串扰直接影响免疫发育的机制，影响炎症和免疫发育的许多其他领域。我们将在慢性心脏移植模型中使用转基因血小板减少和PF4缺陷小鼠来进行我们新颖而有影响力的研究。

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.