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: 10020918
• 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/10020918
• 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; Epithelial Cells; Epithelium; Eragrostis; Exposure to; FOXP3 gene; Generations; Genetic Determinism; 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; central tolerance; dysbiosis; gut microbiota; improved; inflammatory disease of the intestine; knockout animal; microbial; microbial colonization; microbial community; microbiota; mouse model; mucosal microbiota; neonate; normal microbiota; novel strategies; peripheral tolerance; 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。通过胸腺细胞相互作用，在胸腺中，T细胞的指导在胸腺中发生 带有上皮细胞室。胸腺充当免疫T细胞的主要部位 对自我抗原的耐受性和胸腺T调节性（TTREG）细胞的产生，微生物群落 肠道还调节T效应器（TEFF）细胞的功能和周围Treg细胞（PTREG）的产生。 早期生活设施中粘膜组织的微生物定殖对共生和环境的耐受性 抗原。在此期间，异常定殖可能会带来长期后果 粘膜和全身性疾病的发展。调节围产期免疫的机制 实现长期稳态的系统 - 微生物群相互作用的定义很差。我们以前 产生的小鼠（Traf6Δtec），其胸腺没有髓质胸部上皮细胞（MTEC）。 MTEC 耗竭对T细胞输出有两方面的影响：自动反应性T细胞的产生和50％的降低 在ttregs的数量中。 TRAF6ΔTEC小鼠中TTREG的减少依次相关：1）降低 小肠和小肠的peyer斑块（PP）中的Foxp3+ Treg和T卵泡（TF）细胞的数量 小肠注射； 2）偏向于IgA涂层细菌的产生； 3）微生物改变 淘汰动物的肠道中的组成。这些结果在一起表明异常T细胞 在traf6Δtec小鼠的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。在此提案中，我们将使用traf6Δtec 小鼠模型更好地了解T细胞和肠道微生物群如何相互影响以建立 围产期器官特异性公差。我们将测试以下假设：TTREG细胞选择受损 traf6Δtec小鼠，诱导其肠道菌群的变化，无法支持围产期耐受性的诱导 和可行的后代。敲除幼犬的围产期暴露于正常的微生物群需要公差 诱导和生存。为了检验该假设，我们将：1）检查暴露于正常菌群是否为 足以促进新生Traf6ΔTec小鼠的存活并从WT中识别微生物群落 营救Traf6Δtec新生儿存活的小鼠； 2）检查新生儿耐受性是否是 未暴露于正常菌群的新生Traf6ΔTec小鼠中受到损害； 3）检查是否 Traf6ΔTec小鼠的T细胞区室的改变充当肠道营养不良的遗传决定因素和 新生儿致死性。定义早年耐受性机制可能会对我们的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。