Mechanisms and consequences of T cell inflammasome activation in Graft-Versus Host Disease

移植物抗宿主病（GVHD）对于接受造血的人来说仍然是一个重要问题 细胞移植治疗各种癌症、遗传性免疫缺陷和其他疾病。在 GVHD、同种异体反应性 T 细胞介导这种病理学，因为 T 细胞耗尽的造血移植 以免诱发GVHD。我们观察到，移植后，供体 CD8 T 细胞 通过 caspase-1 的激活来测量，经历炎症小体激活。然而，这些 细胞不会通过焦亡而死亡，这可以减轻它们对宿主的细胞毒性后果。我们 还观察到这些炎症小体被激活的细胞过度表达蛋白质， Ifi202 已知可减弱炎症小体激活，与人类 T 细胞类似 表达 IFI16，其在人类细胞中的功能相似。我们假设 Ifi202 限制了 这些细胞中 caspase-1 的激活程度，从而阻止这些细胞经历 细胞焦亡。该项目的目标是确定炎症小体激活的机制 并确定 Ifi202 在预防 CD8 T 细胞焦亡中的作用 GVHD 期间。我们假设这些细胞中 Ifi202 表达的减少将减弱 GVHD 通过增加同种异体反应性 CD8 T 细胞的焦亡来实现病理学。

Graft Versus Host Disease (GVHD) remains a significant issue in people receiving hematopoietic cell transplants to treat various cancers, genetic immunodeficiencies and other diseases. In GVHD, alloreactive T cells mediate this pathology, as T cell depleted hematopoietic transplants to not induce GVHD. We have observed that following transplantation, donor CD8 T cells undergo inflammasome activation, as measured by the activation of caspase‐1. However, these cells do not die via pyroptosis, which may alleviate their cytotoxic consequences in the host. We also observe that these cells in which the inflammasome is activated hyperexpress a protein, Ifi202, which is known to attenuate inflammasome activation, and human T cells similarly express IFI16, which functions similarly in human cells. We hypothesize that Ifi202 limits the degree of caspase‐1 activation in these cells, and thus prevents these cells from undergoing pyroptosis. The goal of this project is to determine the mechanism of inflammasome activation in these T cells, and to determine the role of Ifi202 in preventing pyroptosis in CD8 T cells during GVHD. We hypothesize that reduced Ifi202 expression in these cells will attenuate GVHD pathology by increasing pyroptosis in alloreactive CD8 T cells.