Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice

新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受

• 批准号: 10684667
• 负责人: KONSTANTINA ALEXANDROPOULOS
• 金额: $ 46.23万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684667
• 关键词: Adult; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Bacteria; CD4 Positive T Lymphocytes; Cell Compartmentation; Cells; Cessation of life; Colon; Control Animal; Development; Disease; Epithelial Cells; Epithelium; Exposure to; FOXP3 gene; Generations; Genetic Determinism; Heterozygote; Homeostasis; Human; Immune response; Immune system; Immunoglobulin A; Immunologics; Impairment; Inflammation; Instruction; Intestines; Knock-out; Knockout Mice; Life; Link; Liver; Mediating; Mucous Membrane; Mus; Neonatal; Newborn Infant; Organ; Output; Parents; Perinatal; Perinatal Exposure; Peripheral; Peyer' s Patches; Play; Pregnancy; Process; Production; Regulatory T-Lymphocyte; Role; Site; Small Intestines; Spleen; Structure of thymic medulla; Surface; Systemic disease; T-Cell Activation; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; autoreactive T cell; dysbiosis; effector T cell; gut inflammation; gut microbiota; improved; knockout animal; microbial colonization; microbial community; microbial composition; microbiota; mouse model; mucosal microbiota; neonate; normal microbiota; novel strategies; pup; thymocyte

SUMMARY. Instruction of T cells to be tolerant to self occurs in the thymus through interactions of thymocytes with the epithelial cell compartment. While the thymus serves as the primary site of immunologic T cell tolerance to self-antigens and production of thymic T regulatory (tTreg) cells, microbial communities in the gut also regulate the function of T effector (Teff) cells and production of peripheral Treg cells (pTreg). Microbial colonization of mucosal tissues in early life facilitates tolerance to commensal and environmental antigens. Abnormal colonization during this period can have long-term consequences contributing to development of mucosal and systemic disease later in life. The mechanisms that regulate perinatal immune- system-microbiota interactions to achieve long-term homeostasis are poorly defined. We previously generated mice (Traf6ΔTEC) whose thymus was devoid of medullary thymic epithelial cell (mTECs). mTEC depletion had a two-faceted effect on the T cell output: generation of autoreactive T cells and a 50% reduction in the numbers of tTregs. The reduction in tTregs in Traf6ΔTEC mice in turn associated with: 1) reduced numbers of Foxp3+ Tregs and T follicular (Tf) cells in the Peyer’s Patches (PP) of the small intestine and small intestinal inflammation; 2) skewed production of IgA-coated bacteria; and 3) altered microbial composition in the gut of knockout animals. Together, these results suggest that the aberrant T cell compartment generated in the thymus of Traf6ΔTEC mice and associated changes in the microbiota may adversely impact survival of newborn Traf6ΔTEC mice. In this proposal we will use the Traf6ΔTEC mouse model to better understand how T cells and the gut microbiota influence each other to establish perinatal organ-specific tolerance. We will test the following hypothesis: Impaired tTreg cell selection in Traf6ΔTEC mice, induces changes in their gut microbiota that cannot support induction of perinatal tolerance and viable progeny. Perinatal exposure of knockout pups to normal microbiota is required for tolerance induction and survival. To test this hypothesis we will: 1) examine whether exposure to normal microbiota is sufficient for promoting survival of newborn Traf6ΔTEC mice and identify microbial communities from WT mice that rescue Traf6ΔTEC neonate survival; 2) examine whether induction of neonatal tolerance is compromised in newborn Traf6ΔTEC mice that are not exposed to normal microbiota; and 3) examine if the altered T cell compartment of Traf6ΔTEC mice acts as a genetic determinant of intestinal dysbiosis and neonatal lethality. Defining early-life tolerance mechanisms could have a profound impact on our understanding of human autoimmune disease development and may help us devise novel strategies for managing and/or treating T cell mediated autoimmune diseases.

概括。胸腺中通过胸腺细胞的相互作用指示 T 细胞耐受自身 与上皮细胞区室。而胸腺是免疫 T 细胞的主要部位 对自身抗原的耐受性和胸腺 T 调节 (tTreg) 细胞的产生、微生物群落 肠道还调节效应 T (Teff) 细胞的功能和外周 Treg 细胞 (pTreg) 的产生。 生命早期粘膜组织的微生物定植促进了对共生和环境的耐受 抗原。在此期间的异常定植可能会产生长期后果，导致 晚年出现粘膜和全身疾病。调节围产期免疫的机制 实现长期稳态的系统-微生物群相互作用尚不清楚。我们之前 生成的小鼠（Traf6ΔTEC）的胸腺缺乏髓质胸腺上皮细胞（mTEC）。 mTEC 耗竭对 T 细胞输出产生两个方面的影响：自身反应性 T 细胞的产生和减少 50% tTreg 的数量。 Traf6ΔTEC 小鼠中 tTreg 的减少又与以下因素相关：1) 小肠集合淋巴集结 (PP) 中 Foxp3+ Tregs 和滤泡 T (Tf) 细胞的数量 小肠炎症； 2) IgA 包被细菌的生产存在偏差； 3）改变微生物 基因敲除动物肠道中的成分。总之，这些结果表明异常 T 细胞 Traf6ΔTEC 小鼠胸腺中产生的隔室以及微生物群的相关变化 可能会对新生 Traf6ΔTEC 小鼠的生存产生不利影响。在本提案中，我们将使用 Traf6ΔTEC 小鼠模型，以更好地了解 T 细胞和肠道微生物群如何相互影响，以建立 围产期器官特异性耐受性。我们将检验以下假设： tTreg 细胞选择受损 Traf6ΔTEC 小鼠诱导肠道微生物群发生变化，无法支持诱导围产期耐受性 和可存活的后代。基因敲除幼崽在围产期暴露于正常微生物群是耐受性所必需的 诱导和生存。为了检验这个假设，我们将：1）检查暴露于正常微生物群是否是 足以促进新生 Traf6ΔTEC 小鼠的存活并从 WT 中识别微生物群落 拯救 Traf6ΔTEC 新生儿存活的小鼠； 2) 检查是否诱导新生儿耐受 未接触正常微生物群的新生 Traf6ΔTEC 小鼠受到损害； 3）检查是否 Traf6ΔTEC 小鼠 T 细胞区室的改变是肠道菌群失调的遗传决定因素 新生儿死亡率。定义生命早期的耐受机制可能会对我们产生深远的影响 了解人类自身免疫性疾病的发展，可能有助于我们制定新的策略 管理和/或治疗 T 细胞介导的自身免疫性疾病。