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Expression of gamma delta TCR ligands in development

发育中γδTCR配体的表达

基本信息

批准号：
9332915
负责人：
Wendy L. Havran
金额：
$ 28.88万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-07 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332915
关键词：
Antigens Automobile Driving Candidate Disease Gene Cell Lineage Cell Maturation Cell physiology Cells Coupled DNA Nucleotidylexotransferase Detection Development Disease Embryo Environmental Risk Factor Epidermis Epithelial Epithelial Cells Fetal Development Gene Expression Gene Expression Profiling Genes Genetic Recombination Individual Inflammatory Injury Interferon Type II Interleukin-17 Knowledge Ligands Location Lymphoid Mediating Modeling Mus Nomenclature Peptide Signal Sequences Play Population Positioning Attribute Process Production Role SOX13 gene Series Signal Transduction Site Skin Skin Neoplasms Stress T-Cell Receptor T-Lymphocyte Techniques Therapeutic Thymic epithelial cell Thymus Gland Tissues Transferase Wound Healing assault base experimental study fetal functional plasticity improved keratinocyte killings novel prototype residence response thymocyte tool tumor γδ T cells

项目摘要

Individual TCR γ and δ genes are rearranged and expressed in a series of overlapping waves during murine development with cells bearing specific TCR preferentially or exclusively migrating from the thymus to specific epithelial and lymphoid sites. γδ T cells that rearrange their TCR during early fetal development express highly restricted or invariant TCR. The first TCR-bearing cells migrate from the developing thymus to the skin where they take up residence in the epidermis as Thy-1+ dendritic epidermal T cells (DETC). Similarly, subsequent waves of γδ TCR expressing thymocytes migrate to other epithelial tissues. The presence of these γδ T cell populations with restricted TCR use in distinct epithelial locations supports recognition of unique, tissue- specific antigens and specialized functions for these cells. However, roles for TCR signals in development and ligands for these invariant γδ TCRs are currently poorly understood. We hypothesize that novel endogenous Vγ3Vδ1 TCR ligands are expressed in the embryonic thymus and deliver key signals for DETC precursor development and that expression of these ligands is upregulated on skin epithelial cells following stress and functions to deliver activation signals to DETC following injury or stress. We have developed tools for detection of Vγ3Vδ1 TCR ligands and found expression on embryonic, but not adult, thymic epithelial cells. Based upon these results, we are now in a position to identify and characterize this fetal TCR ligand and determine its role in DETC precursor development and activation of DETC function.

单个TCR γ和δ基因在小鼠免疫过程中重排并以一系列重叠波表达。具有特异性TCR的细胞优先或排他地从胸腺迁移到特异性TCR的发育上皮和淋巴样部位。在早期胎儿发育过程中重排TCR的γδ T细胞表达高水平的限制性或不变的TCR。第一个携带TCR的细胞从发育中的胸腺迁移到皮肤，它们作为Thy-1+树突状表皮T细胞（DETC）驻留在表皮中。同样，随后表达γδ TCR的胸腺细胞向其他上皮组织迁移。这些γδ T细胞的存在在不同的上皮位置限制TCR使用的人群支持识别独特的组织- 这些细胞的特异性抗原和特殊功能。然而，TCR信号在发育和这些不变γδ TCR的配体目前知之甚少。我们假设新的内源性 Vγ3Vδ1 TCR配体在胚胎胸腺中表达并传递DETC前体的关键信号这些配体的表达在应激后在皮肤上皮细胞上上调，功能是在受伤或压力后向DETC传递激活信号。我们已经开发了工具，检测到Vγ3Vδ1 TCR配体，发现在胚胎而非成人胸腺上皮细胞上表达。基于这些结果，我们现在能够鉴定和表征这种胎儿TCR配体，确定其在DETC前体发育和DETC功能激活中的作用。