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中的研究已经使人们认识到，在免疫应答的引发阶段期间抗原（Ag）密度的变化可能对T细胞应答的特征和最终结果产生显著影响。例如，来自LCMV系统的证据表明，病毒载量的程度严重影响应答T细胞的功能和命运，增加的病毒载量与细胞因子表达减少和最终功能衰竭相关。暴露于Ag的增加导致Ag特异性T细胞以离散的分级方式逐渐丧失功能。结果，Ag特异性T细胞无法控制病毒。此外，在自身免疫性糖尿病小鼠模型中的研究表明，增加的Ag表达导致CD 8 + T细胞区室中更快和更完全的耐受诱导。 相反，对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密度的影响知之甚少。虽然在病毒环境中，慢性Ag暴露引起的T细胞耗竭是不利的，但这种形式的Ag诱导的耗竭可能导致有利的结果和移植后供体特异性耐受性增加。Ag密度的问题在移植研究中是非常重要的，因为allo-Ag的Ag密度可以跨越比标称Ag的Ag密度宽得多的范围。因此，我们建议表征在免疫应答的引发阶段期间Ag密度对应答T细胞群体的功能和适应性的影响。具体而言，我们将评估Ag密度对皮肤移植物排斥反应动力学和供体特异性CD 4+和CD 8 + T细胞编程的影响，并确定Ag密度变化对CD 28和CD 40 L阻断诱导供体特异性耐受和长期皮肤移植物接受能力的影响。此外，我们建议表征在耐受诱导期间Ag密度对Ag特异性T细胞上PD-1表达的动力学和需求的影响。 器官移植代表了多种形式的终末期器官疾病的治愈性疗法。随着移植手术技术的改进，需要更好的策略来防止移植器官的排斥，以提高长期移植物存活率，最小化抗排斥药物的副作用，并减少重新移植的需要。本申请中提出的研究将为移植排斥反应的机制提供急需的见解，并希望实现这些目标。

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.