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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：
10229524
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/10229524
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 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&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 central tolerance dysbiosis effector T cell gut microbiota improved inflammatory disease of the intestine knockout animal microbial colonization microbial community microbial composition microbiota mouse model mucosal microbiota neonate normal microbiota novel strategies peripheral tolerance 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.

总结。T细胞耐受自身的指令发生在胸腺中，通过胸腺细胞的相互作用