Antigenic specificities of intestinal CD4+Foxp3+ T cells.

肠道 CD4 Foxp3 T 细胞的抗原特异性。

• 批准号: 9006761
• 负责人: LESZEK IGNATOWICZ
• 金额: $ 38万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9006761
• 关键词: Address; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antigenic Specificity; Antigens; Biology; CD4 Positive T Lymphocytes; Cells; Clonal Expansion; Communities; Diet; Equilibrium; Exposure to; Food; Frequencies; Goals; Green Fluorescent Proteins; High-Throughput Nucleotide Sequencing; Homeostasis; Homing; Immune system; Individual; Inflammatory disease of the intestine; Intestines; Life; Maintenance; Mouse Strains; Mus; Mutation; Neonatal; Newborn Infant; Organ; Peripheral; Play; Population; Property; Regulation; Regulatory T-Lymphocyte; Reporter; Research; Role; Shapes; Signal Transduction; Specificity; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tropism; adaptive immunity; base; commensal microbes; complementarity-determining region 3; design; improved; in vivo; intestinal homeostasis; member; microbial; microbiota; microorganism antigen; mouse model; neonatal exposure; peripheral tolerance; postnatal; research study; resistant strain; response; transcription factor; young adult

In the intestine, regulatory T cells that express Foxp3 transcription factor (Tregs) are critical for the regulation of adaptive immune response to commensal antigens. Tregs differentiate in the thymus (tTregs) or convert from naive, peripheral Foxp3- T cells (pTregs).It is currently unclear if tTregs and pTregs have redundant or complimentary role in maintenance of intestinal homeostasis. Our long term goal is to understand how the homeostatic balance in the intestine depends on pTregs and tTregs, and how their TCR repertoires can change by exposure to antibiotics. Our central hypothesis is that clonal expansions and selective trophism of tTregs are essential to sustain intestinal equilibrium. To test our hypothesis we propose two specific aims. First we will characterize TCRs on mucosal Tregs in the intestine of CNS1mut mice that lack pTregs but have normal tTregs. In addition, in these mice CD4+ T cells express semi diverse repertoire of TCRs and activated Tregs express green fluorescent protein (GFP). We hypothesize that in these mice mucosal tTregs will control intestinal naïve and effector T cells, and that TCRs expressed by tTregs can be specific to commensal antigens. Second, we will investigate how antibiotic treatment early in life can permanently change microbial flora and clonal diversity of intestinal Tregs. We hypothesize that changes in the diversity for microbial flora induced by neonatal exposure to antibiotics permanently alter repertoire of intestinal tTregs.

在肠道中，表达 Foxp3 转录因子 (Treg) 的调节性 T 细胞对于 对共生抗原的适应性免疫反应的调节。 Tregs 的差异在于 胸腺 (tTregs) 或由幼稚外周 Foxp3- T 细胞 (pTregs) 转化而来。目前尚不清楚 如果 tTreg 和 pTreg 在维持肠道功能方面具有冗余或互补作用 体内平衡。我们的长期目标是了解肠道内的稳态平衡如何 取决于 pTreg 和 tTreg，以及它们的 TCR 功能如何因暴露于 抗生素。我们的中心假设是 tTreg 的克隆扩增和选择性营养作用是 对维持肠道平衡至关重要。为了检验我们的假设，我们提出了两个具体目标。 首先，我们将表征 CNS1mut 小鼠肠道粘膜 Tregs 上的 TCR，这些小鼠缺乏 pTregs 但具有正常的 tTregs。此外，在这些小鼠中，CD4+ T 细胞表达半多样性 TCR 和激活的 Tregs 的全部功能表达绿色荧光蛋白 (GFP)。我们 假设这些小鼠的粘膜 tTregs 将控制肠道幼稚 T 细胞和效应 T 细胞， tTreg 表达的 TCR 可以特异性针对共生抗原。其次，我们将 研究生命早期的抗生素治疗如何永久改变微生物菌群， 肠道 Tregs 的克隆多样性。我们假设微生物多样性发生变化 新生儿接触抗生素诱导的菌群会永久改变肠道 tTreg 的功能。