Exploratory Study of T Cell Skin Trafficking and the Role of NKG2D Signaling; Implications in Vitiligo and Melanoma

摘要 在免疫学领域，T细胞迁移被认为对宿主的长期存活至关重要。然而， 参与的参与者和这个复杂网络中的机械关系仍有待完全建立，特别是 在白癜风和黑色素瘤的背景下。我们对T细胞迁移特性和起始时间的了解可能有助于 找到临床上适用于白癜风和黑色素瘤的治疗方法。基于新的初步数据，我们建议研究 NKG 2D信号传导作为T细胞运输的贡献者。这项研究的科学前提来自我们的工作 这表明NKG 2D的缺乏降低了T细胞的迁移和CCR 4的表达。我们假设NKG 2D 通过精细调节的DAP 10 PI 3 K/Grb 2信号传导控制CD 8 T细胞运输（因为NKG 2D本身不能发出信号 使用DAP 10 PI 3 K/Grb 2作为信号转导衔接子），其控制CCR 4的表达。该提案将确定基本的 NKG 2D-DAP 10 PI 3 K和-DAP 10 Grb 2在CD 8 T细胞运输和CCR 4表达调控中的作用。这里我们将 利用人类和小鼠模型进行实验测试。 SA 1.确定控制NKG 2D-DAP 10 PI 3 K和/或-DAP 10 Grb 2的信号路径 CCR 4表达。 SA 2.确定NKG 2D-DAP 10 PI 3 K和/或-DAP 10 Grb 2的比贡献 CD 8 T细胞的皮肤运输中的信号传导。

Abstract In the field of immunology, T cell migration is considered crucial for long-term host survival. However, the identity of the players that participate and the mechanistic relationships in this complex network remain to be fully established, especially in the context of vitiligo and melanoma. Our understanding of the T cell migratory properties and initiation ques may help find clinically applicable treatments to vitiligo and melanoma. Based on novel preliminary data, we propose to study NKG2D signaling as a contributor to T cell trafficking. The scientific premise of this study is derived from our work demonstrating that lack of NKG2D reduces T cell tmigration and expression of CCR4. We hypothesize that NKG2D controls CD8 T cell trafficking through a finely tuned DAP10PI3K/Grb2 signaling (as NKG2D cannot signal by itself instead of using DAP10PI3K/Grb2 as signaling adaptor) that controls the expression of CCR4. This proposal will define the underlying roles of NKG2D-DAP10PI3K and -DAP10Grb2 in CD8 T cell trafficking and the expression control of CCR4. Here we will conduct experimental tests utilizing human and mouse models. SA1. TO DETERMINE THE SIGNALING PATH FOR NKG2D-DAP10PI3K and/or -DAP10Grb2 THAT CONTROLS CCR4 EXPRESSION. SA2. TO DETERMINE THE SPECIFIC CONTRIBUTION OF NKG2D-DAP10PI3K and/or -DAP10Grb2 SIGNALING IN THE SKIN TRAFFIC OF CD8 T CELLS.