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细胞优先驻留在覆盖身体内外表面的上皮组织中，在那里它们在第一道防线中发挥作用，例如炎症调节、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，我们将尝试揭示皮肤中γ/δ T细胞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V γ 3/V δ 1 T细胞受体，并起源于胎儿胸腺。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协调转换相关，这组趋化因子受体对它们在皮肤中的外周组织分布可能是重要的。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胎儿胸腺选择过程的γ/δ T细胞，在其独特的归巢特性和皮肤特异性组织分布的关系，并确定积极的选择相关的CCR 10上调和CCR 6下调sIEL的发展。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，在那里它们被定位以对抗感染和肿瘤生长。这些知识将有助于找到一种将免疫细胞引导到特定组织以治疗不同疾病的方法。 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，在机体抵御疾病的第一道防线中发挥着重要作用。本文拟研究一类皮肤特异性淋巴细胞群的发育机制。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，在那里它们被定位以对抗各种疾病。

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.