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

描述（由申请人提供）：与α / β T细胞不同，γ / δ T细胞优先存在于覆盖身体外部和内部表面的上皮组织中，在那里它们起着第一道防线的作用，如炎症调节、肿瘤监测和组织修复。利用转基因和敲除小鼠模型作为实验方法，我们将试图揭示γ / δ T细胞在皮肤中发育和特定组织分布的分子机制。几乎所有的皮肤γ / δ T细胞表达相同的vγ - 3/ vδ - 1 T细胞受体，起源于胎儿胸腺。胎儿胸腺中γ / δ T细胞的阳性选择与一组趋化因子受体表达的坐标开关有关，这些趋化因子受体在皮肤中的外周组织分布可能很重要。为了进一步了解这一过程，我建议解剖TCR/配体相互作用介导的γ / δ T细胞的胎儿胸腺选择过程，以及它们独特的归巢特性和皮肤特异性组织分布的关系，并确定sIEL发育中CCR10上调和CCR6下调的正选择。这些研究将有助于了解免疫细胞如何进入不同的局部组织，在那里它们被定位来对抗感染和肿瘤生长。这一知识将有助于找到一种方法，将免疫细胞引导到特定组织，以治疗不同的疾病。

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.