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

移植物抗宿主病（GVHD）仍然是接受造血干细胞移植的人的一个重要问题。 细胞移植来治疗各种癌症、遗传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，因为T细胞耗尽造血移植 不诱发GVHD我们观察到移植后，供体CD 8 T细胞 经历炎性小体活化，如通过半胱天冬酶-1的活化所测量的。但这些 细胞不会通过焦亡而死亡，这可以减轻它们在宿主中的细胞毒性后果。我们 还观察到其中炎性小体被激活的这些细胞超表达蛋白质， 已知可减弱炎性小体活化的Ifi 202和人T细胞类似 表达IFI 16 β，其在人类细胞中具有类似的功能。我们假设Ifi 202限制了 在这些细胞中的caspase-1活化程度，从而防止这些细胞经历 焦亡本项目的目标是确定炎性小体激活的机制 并确定Ifi 202在预防CD 8 T细胞中的焦亡中的作用 移植物抗宿主病我们假设这些细胞中Ifi 202表达的降低将减弱GVHD 病理学通过增加同种异体反应性CD 8 T细胞中的焦亡来实现。

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.