Effects of breast milk antibodies on neonatal intestinal immunity and host-microbe mutualism

项目概要/摘要 母乳是生命早期宿主-微生物组相互作用的关键调节剂。除了营养成分，母乳 含有细胞因子、生长因子和抗体，有助于塑造微生物群的组成， 调节婴儿对肠道微生物的免疫力。越来越多的证据表明母乳喂养与降低 在以后的生活中发展免疫介导的和代谢性疾病。然而，乳房的具体成分 目前缺乏牛奶和这些联系背后的机制。使用小鼠模型，我们的实验室 发现缺乏母乳抗体的小鼠增加了粘膜T细胞依赖性免疫， 反应，包括肠道引流中T滤泡辅助（Tfh）细胞和生发中心（GC）B细胞的升高 淋巴组织这一过程是由微生物驱动的，而缺乏母乳抗体的无菌小鼠则没有 产生异常的粘膜Tfh和GC B细胞应答。由于肠道微生物群的深刻影响， 免疫系统的发展与活化的适应性免疫细胞的终身持续性相结合， 目前的一种模式是，对肠道细菌的不适当的适应性免疫反应会导致不良健康状况， 长期的结果。这一建议的假设是，不适当的适应性免疫反应， 由于缺乏母乳抗体而导致的常驻肠道细菌会导致 肠内稳态为了验证这一假设，提出了两个目标。目标1研究了持久性， 定位和表型的B细胞激活的母源抗体的情况下，通过命运跟踪激活 GC B细胞和流式细胞术。目的2评价T细胞依赖性适应性免疫应答的功能 肠道内环境稳定新型T细胞的综合表型和功能表征 在缺乏母乳抗体的新生儿中出现的依赖性免疫应答将提供关键机制， 了解母乳喂养如何有助于长期健康。这里概述的研究将奠定基础 用于开发干预和疗法，以操纵宿主与微生物群的关系， 促进长期健康，特别是非母乳喂养的新生儿。

Project Summary/Abstract Breast milk is a key regulator of host-microbiome interactions in early life. In addition to nutrients, breast milk contains cytokines, growth factors and antibodies, which help shape the composition of the microbiota and regulate infant immunity to gut microbes. Accumulating evidence links breastfeeding with a decreased risk of developing immune-mediated and metabolic diseases later in life. However, the specific components of breast milk and the mechanism underlying these associations are currently lacking. Using a mouse model, our lab discovered that mice deficient in breast milk antibodies mount increased mucosal T cell- dependent immune responses, including elevated T follicular helper (Tfh) cells and germinal center (GC) B cells in the gut-draining lymphoid tissues. This process is driven by microbes as germ-free mice lacking breast milk antibodies do not generate aberrant mucosal Tfh and GC B cell responses. Due to the profound impact of the gut microbiota on the development of the immune system coupled with the lifelong persistence of activated adaptive immune cells, a current paradigm is that inappropriate adaptive immune responses to gut bacteria drive adverse health outcomes in the long-term. The hypothesis of this proposal is that inappropriate adaptive immune responses to resident gut bacteria resulting from the absence of breast milk antibodies drives persistent impairments in intestinal homeostasis. To test this hypothesis, two aims are proposed. Aim 1 investigates the persistence, localization, and phenotype of B cells activated in the absence of maternal antibodies via fate-tracking activated GC B cells and flow cytometry. Aim 2 assesses the function of the T cell dependent adaptive immune response on intestinal homeostasis. The comprehensive phenotypic and functional characterization of the novel T cell dependent immune response that arises in neonates lacking breast milk antibodies will provide key mechanistic insight on how breastfeeding contributes to long-term health. The studies outlined here will lay the groundwork for the development of interventions and therapies to manipulate host relationships with the microbiota and promote long-term health, particularly in neonates who are not breastfed.