T Cell Memory in Organ Transplantation

描述（由申请人提供）：排斥过程的关键步骤是抗供体效应T细胞或记忆T细胞向移植器官的迁移。中断这一步骤应该可以预防或减弱排斥反应，但目前还没有安全的临床策略来做到这一点。在之前的资助周期中，我们确定了抗供体效应T细胞和记忆T细胞迁移到血管化器官移植物的关键途径。我们证明了供体抗原，由移植物内皮细胞或骨髓来源的抗原呈递细胞呈递，对于抗供体T细胞的牢固粘附和跨内皮迁移是必要和充分的。不需要通过G¿i偶联趋化因子受体进行信号传导。在这次拨款更新中，我们建议研究抗原驱动T细胞迁移的两个新方面：(1)移植物抗原呈递细胞的作用，(2)tcr触发的信号通路的作用，导致T细胞粘附和迁移。为了实现这些目标，我们将利用心脏和肾脏小鼠移植模型，抗原呈递或关键信号通路被破坏的基因敲除小鼠，以及实时跟踪迁移T细胞的活体成像技术。提出的研究具有创新性和重要意义，因为它们代表了从经典的趋化因子依赖迁移范式的转变，并提供了以特定和安全的方式中断活化T细胞迁移的新机会。

DESCRIPTION (provided by applicant): A critical step in the rejection process is the migration of anti-donor effector or memory T cells to the transplanted organ. Interrupting this step should prevent or weaken rejection, but safe clinical strategies to do so are not available. During the previous funding cycle we identified a key pathway by which anti-donor effector and memory T cells migrate to vascularized organ allografts. We demonstrated that donor antigen, presented by either graft endothelial cells or bone marrow-derived antigen presenting cells, is necessary and sufficient for the firm adhesion and trans-endothelial migration of anti-donor T cells. Signaling via G¿i-coupled chemokine receptors was not required. In this grant renewal, we propose to investigate two novel aspects of antigen-driven T cell migration: (1) the role of graft antigen presenting cells, and (2) the role of TCR-triggered signaling pathways that cause T cell adhesion and transmigration. To accomplish these aims we will utilize heart and kidney mouse transplantation models, gene knockout mice in which antigen presentation or key signaling pathways are disrupted, and intravital imaging techniques that track migrating T cells in real time. The proposed studies are innovative and significant because they represent a shift from the classical, chemokine-dependent migration paradigm and provide novel opportunities for interrupting activated T cell migration in a specific and safe manner.