IRF4-dependent T-cell effector programs in governing transplant outcomes

项目摘要 实体器官移植是终末期器官衰竭患者的救命治疗，但长期以来， 同种异体移植物的长期存活受到免疫排斥和免疫抑制药物副作用的限制。 同种异体T细胞反应是移植结果的核心（排斥与耐受）。因此 这对于定义影响移植结果的T细胞效应程序至关重要。 我们最近发现，干扰素调节因子4（IRF4）是一个关键的转录决定因子， 控制移植中的同种异体T细胞应答。T细胞中的IRF4缺失导致进行性 建立CD4+ T细胞功能障碍和长期心脏移植物存活。这些发现 已被《豁免权》杂志接受出版。在此，我们假设IRF4调控移植， 通过控制T细胞功能的核心调节回路来控制结果。因此，中央重点 该提议的一个重要目的是鉴定同种异体反应性效应T细胞中IRF4控制的调节回路。

Project Summary Solid organ transplantation is a lifesaving treatment for patients with end-stage organ failure, but long- term allograft survival is limited by immune rejection and side effects of immunosuppressive drugs. Allogeneic T cell responses are central to transplant outcomes (rejection versus tolerance). It is thus essential to define the T cell effector programs that affect the transplant outcomes. We recently discovered that interferon regulatory factor 4 (IRF4) is a key transcriptional determinant controlling allogenic T cell response in transplantation. IRF4 deletion in T cells results in progressive establishment of CD4+ T cell dysfunction and long-term cardiac allograft survival. These findings have been accepted for publication in Immunity. Herein, we hypothesized that IRF4 governs transplant outcomes through controlling the core regulatory circuits of T cell function. Therefore, the central focus of this proposal is to identify the IRF4 controlled regulatory circuits in alloreactive effector T cells.