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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

摘要：胸腺中通过胸腺细胞的相互作用指示 T 细胞耐受自身。与上皮细胞区室相比，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在此期间的异常定植可能会产生长期后果，导致晚年粘膜和全身疾病的发展。调节围产期免疫的机制。我们之前对系统-微生物群相互作用以实现长期稳态的定义不明确。产生的小鼠（Traf6ΔTEC）的胸腺缺乏髓质胸腺上皮细胞（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 50% 的减少 Traf6ΔTEC 小鼠中 tTreg 数量的减少又与以下因素相关：1) 减少小肠集合淋巴集结 (PP) 中 Foxp3+ Tregs 和滤泡 T (Tf) 细胞的数量小肠炎症；2) IgA 包被细菌的产生偏差；3) 微生物改变；基因敲除动物肠道中的成分共同表明，T 细胞存在异常。 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敲除幼崽的围产期暴露于正常微生物群是耐受的必要条件。为了检验这一假设，我们将：1）检查是否接触正常微生物群。足以促进新生 Traf6ΔTEC 小鼠的存活并从 WT 中识别微生物群落挽救 Traf6ΔTEC 新生儿存活的小鼠；2) 检查新生儿耐受性的诱导是否有效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。