T Cell Memory in Organ Transplantation

描述(申请人提供)：排斥过程中的一个关键步骤是抗供体效应器或记忆T细胞向移植器官的迁移。阻断这一步骤应该可以防止或减弱排斥反应，但目前还没有安全的临床策略来做到这一点。在前一个资助周期中，我们确定了一条关键途径，通过该途径，抗供者效应器和记忆T细胞迁移到带血管的同种异体器官。我们证明，供体抗原由移植物内皮细胞或骨髓来源的抗原提呈细胞提呈，对于抗供体T细胞的牢固黏附和跨内皮细胞迁移是必要和充分的。不需要通过G？I偶联趋化因子受体来传递信号。在这次赠款更新中，我们建议研究抗原驱动的T细胞迁移的两个新方面：(1)移植物抗原提呈细胞的作用，(2)TCR触发的信号通路导致T细胞黏附和迁移的作用。为了实现这些目标，我们将利用小鼠心脏和肾脏移植模型、抗原呈递或关键信号通路被扰乱的基因敲除小鼠，以及实时跟踪迁移T细胞的活体成像技术。所提出的研究具有创新性和重要意义，因为它们代表了经典的趋化因子依赖的迁移范式的转变，并为以特定和安全的方式阻断激活的T细胞迁移提供了新的机会。

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.