Antigen Density Critically Impacts T Cell Programming During Transplantation

描述(由申请人提供)：最近在非移植病毒感染和自身免疫模型系统方面的工作使人们了解到，免疫反应启动阶段抗原(Ag)密度的变化可以对T细胞反应的特征和最终结果产生重大影响。例如，来自LCMV系统的证据表明，病毒载量的程度严重影响反应T细胞的功能和命运，病毒载量增加与细胞因子表达减少和最终功能衰竭相关。暴露于Ag的增加会导致Ag特异性T细胞以离散的层级方式逐渐丧失功能。其结果是，抗原特异性T细胞无法控制病毒。此外，对自身免疫性糖尿病小鼠模型的研究表明，抗原表达增加导致CD8+T细胞更快、更完全地诱导耐受。 相反，关于同种异体移植排斥反应期间执行的指导性发育T细胞程序以及它们是否受Ag浓度的影响，人们知之甚少。虽然在病毒环境中，慢性Ag暴露导致的T细胞耗尽是不利的，但这种由Ag诱导的耗竭形式可能会在移植后带来良好的结果和提高供者的特异性耐受性。在移植研究中，Ag浓度的问题是非常重要的，因为异体Ags的Ag浓度可能比标称Ags的范围宽得多。因此，我们建议表征免疫反应启动阶段的抗原密度对反应T细胞群的功能和适合性的影响。具体地说，我们将评估Ag浓度对皮肤移植排斥反应动力学和供者特异性CD4+和CD8+T细胞编程的影响，并确定Ag浓度的变化对CD28和CD40L阻断诱导供者特异性耐受和长期皮肤移植接受能力的影响。此外，我们建议表征在耐受诱导过程中，抗原密度对抗原特异性T细胞上PD-1表达的动力学和需求的影响。 摘要：器官移植是多种终末期器官疾病的根治方法。随着移植外科技术的改进，需要更好的策略来预防移植器官的排斥反应，以提高移植物的长期存活率，最大限度地减少抗排斥药物的副作用，并减少再次移植的需要。这项申请中提出的研究将为移植排斥反应的机制提供亟需的见解，并有望实现这些目标。

DESCRIPTION (provided by applicant): Recent work in non-transplant viral infection and autoimmune model systems has led to the understanding that variations in antigen (Ag) density during the priming phase of the immune response can have significant effects on the character and ultimate outcome of a T cell response. For example, evidence from the LCMV system demonstrates that the degree of viral load critically impacts the function and fate of the responding T cells, with increased viral loads being associated with reduced cytokine expression and eventual functional exhaustion. Increased exposure to Ag causes Ag-specific T cells to progressively lose function in a discrete hierarchical fashion. As a result, Ag-specific T cells are rendered unable to control the virus. In addition, studies in mouse models of autoimmune diabetes have revealed that increased Ag expression resulted in faster and more complete tolerance induction in the CD8+ T cell compartment. Conversely, relatively little is known about the instructional developmental T cell programs that are executed during allograft rejection and whether they are influenced by Ag density. While T cell exhaustion that occurs from chronic Ag exposure is unfavorable in a viral setting, this form of Ag-induced exhaustion may lead to favorable outcomes and increased donor-specific tolerance following transplantation. The issue of Ag density is very important in the study of transplantation, as the Ag density of allo-Ags may span a much broader range than that of nominal Ags. Therefore, we propose to characterize the effects of Ag density during the priming phase of the immune response on the function and fitness of the responding T cell population. Specifically, we will assess the effect of Ag density on the kinetics of skin graft rejection and programming of donor-specific CD4+ and CD8+ T cells, and determine the impact of variations in Ag density on the ability of CD28 and CD40L blockade to induce donor-specific tolerance and long-term skin graft acceptance. In addition, we propose to characterize the impact of Ag density on the kinetics of and requirement for PD-1 expression on Ag-specific T cells during tolerance induction. Lay Summary: Organ transplantation represents a curative therapy for many forms of end-stage organ disease. As surgical techniques for transplantation are improved, better strategies to prevent rejection of transplanted organs are needed in order to improve long-term graft survival, minimize the side-effects of anti- rejection medications, and reduce the need to re-engraftment. The research proposed in this application will provide much-needed insight into the mechanisms of transplant rejection, with the hopes of achieving these goals.