Positive Selection-Dependent Skin-Homing of Fetal Thymic Gamma/Delta T Cells

描述(申请人提供)：与阿尔法/贝塔T细胞不同，伽马/德尔塔T细胞优先驻留在覆盖身体内外表面的上皮组织中，在那里它们发挥第一道防线的功能，如调节炎症、肿瘤监视和组织修复。使用转基因和基因敲除小鼠模型作为实验方法，我们将试图揭示皮肤中伽马/Delta T细胞发育和特定组织分布的分子机制。几乎所有的皮肤伽马/增量T细胞都表达相同的VGamma3/Vdelta1 T细胞受体，并且来源于胎儿胸腺。胎儿胸腺中γ/Delta T细胞的阳性选择与一组趋化因子受体表达的坐标切换有关，这些趋化因子受体对其在皮肤中的外周组织分布具有潜在的重要作用。为了进一步了解这一过程，我建议剖析TCR/配体相互作用介导的胎儿胸腺选择伽马/Delta T细胞的过程，及其与其独特的归巢特性和皮肤特异性组织分布的关系，并确定与CCR10上调和CCR6下调相关的正选择在SIEL发育中的作用。这些研究将有助于理解免疫细胞如何进入不同的局部组织，在那里它们处于对抗感染和肿瘤生长的位置。这些知识将有助于找到一种方法，将免疫细胞定向到特定组织，以治疗不同的疾病。 公共卫生相关性：组织特异性淋巴细胞是免疫系统的重要组成部分，在抵御疾病的第一道防线中发挥着重要作用。在此，我建议研究一类皮肤特异性淋巴细胞的发育机制。这些研究将有助于理解免疫细胞如何进入不同的局部组织，在那里它们处于对抗各种疾病的位置。

DESCRIPTION (provided by applicant): Unlike alpha/beta T cells, gamma/delta T cells preferentially reside in epithelial tissues covering the external and internal surface of a body, where they function in the first line of defense, such as regulation of inflammation, tumor surveillance and tissue repairing. Using transgenic and knockout mouse models as experimental approaches, we will try to uncover molecular mechanisms underlying development and specific tissue distribution of gamma/delta T cells in the skin. Nearly all skin gamma/delta T cells express identical Vgamma3/Vdelta1 T cell receptors and originate from the fetal thymus. Positive selection of gamma/delta T cells in the fetal thymus is associated with a coordinate switch in expression of a set of chemokine receptors potentially important for their peripheral tissue distribution in the skin. To further understand this process, I propose to dissect the TCR/ligand interaction-mediated fetal thymic selection process of gamma/delta T cells, in relationship with their unique homing properties and skin-specific tissue distribution and determine the positive selection associated CCR10 upregulation and CCR6 downregulation in sIEL development. These studies will help understand how immune cells go to different local tissues where they are positioned to fight against infection and tumor growth. This knowledge will be useful in helping to find a way to direct immune cells to specific tissues to treat different diseases. PUBLIC HEALTH RELEVANCE: Tissue specific lymphocytes are important components of immune system and play an important role in the first line of defense against diseases. I propose here to study developmental mechanism of a class of skin-specific lymphocyte populations. These studies will help understand how immune cells go to different local tissues where they are positioned to fight against various diseases.