How Proinflammatory Cytokines Block T Cell Death In Vivo

描述（由申请人提供）：我们的目标是确定来自toll样受体（TLR）刺激的促炎细胞因子和因子如何影响体内特异性CD4 T细胞免疫。表征这一过程将通过定义新的方法来控制体内T细胞反应，同时最大限度地减少毒性，从而改善佐剂的发展。这个目标是基于我们最近的工作，它揭示了TLR4适配器之间意想不到的分工。一条途径标志着T细胞效应分化和归巢到实体器官，另一条途径负责克隆扩增和诱导细胞存活。因此，揭示TLR4途径产生的佐剂反应如何影响T细胞行为，将使疫苗学家能够对ag特异性CD4 T细胞施加理想的影响。这一目标将通过确定每个接头如何影响T细胞的机制来实现。在目标1中，我们将通过检查先天细胞因子轴来确定TRIF如何控制T细胞效应分化和归巢，我们假设这两种细胞行为都有增强作用。这一目标的数据将有助于设计疫苗配方，这将有助于驱动效应T细胞迁移到身体的特定部位。在Aim 2中，将捕获注定存活的特定CD4 T细胞的蛋白质组学图，并将其与相同的特定T细胞进行对比。我们将使用一种创新的液体分离方法来实现这一目标，这种方法将允许我们挖掘这些群体之间的差异变化的蛋白质组。Aim 3将利用我们的新发现，证明ag经历的CD4 T细胞可以促进佐剂毒性。我们将定义这一过程，并开发新的方法来对抗毒性，同时促进强佐剂反应。因此，本提案的结果将提供一个“辅助毒性”比率，可用于衡量TLR激动剂的有效性和安全性，并重要地为设计辅助治疗提供循证方法。

DESCRIPTION (provided by applicant): Our goal is to define how pro-inflammatory cytokines and factors derived from toll-like receptor (TLR) stimulation impact specific CD4 T cell immunity in vivo. Characterizing this process will improve adjuvant development by defining new methods to control in vivo T cell responses while minimizing toxicity. This goal is based on our recent work which unveiled an unexpected division of labor between the TLR4 adaptors. One path signaled T cell effector differentiation and homing to solid organs, and the other path was responsible for clonal expansion and inducing cell survival. Therefore, uncovering how the adjuvant response emanating from the TLR4 pathway affects T cell behavior will allow vaccinologists to push desirable effects on Ag-specific CD4 T cells. This goal will be accomplished in 3 specific aims by determining the mechanism of how each adaptor impacts T cells. In Aim 1 we will determine how TRIF controls T cell effector differentiation and homing by examining an innate cytokine axis that we hypothesize potentiates both cell behaviors. Data from this aim will help design vaccine formulations that will aid in driving effector T cell migration to specific sites of the body. In Aim 2 a proteomic map of specific CD4 T cells destined to survive will be captured and contrasted to the same specific T cells programmed to die. We will accomplish this goal using an innovative liquid fractionation approach that will permit us to mine the proteome for differential changes between these populations. Aim 3 will capitalize on our novel finding demonstrating that Ag-experienced CD4 T cells can facilitate adjuvant toxicity. We will define this process and develop new approaches to counter toxicity while promoting strong adjuvant responses. Thus, the results from this proposal will provide an "adjuvant to toxicity" ratio that can be used to gauge the effectiveness and safety of TLR agonists, and importantly provide an evidence-based approach to designing adjuvant therapeutics.