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

项目摘要/摘要 母乳是早期生命中宿主-微生物群相互作用的关键调节器。除了营养，母乳 含有细胞因子、生长因子和抗体，它们有助于塑造微生物区系的组成和 调节婴儿对肠道微生物的免疫力。越来越多的证据表明，母乳喂养与降低患糖尿病的风险有关 在晚年患上免疫调节和代谢性疾病。然而，乳房的特定成分 牛奶和这些关联背后的机制目前还缺乏。使用老鼠模型，我们的实验室 发现母乳抗体缺乏的小鼠增加了粘膜T细胞依赖的免疫 反应，包括肠道引流中T滤泡辅助细胞(TFH)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，因为没有母乳抗体的无菌小鼠不会 产生异常的粘膜Tfh和GC B细胞反应。由于肠道微生物区系对 免疫系统的发展伴随着激活的适应性免疫细胞的终身存在， 目前的一个范例是，对肠道细菌的不适当的适应性免疫反应会导致不利的健康 长期的结果。这项建议的假设是，不适当的适应性免疫反应 由于缺乏母乳抗体而导致的肠道细菌持续损害 肠道内环境平衡。为了验证这一假说，我们提出了两个目标。目标1调查的是持久性， 通过命运跟踪激活的B细胞在无母体抗体时的定位和表型 GC B细胞和流式细胞仪检测。目的2评估T细胞依赖的适应性免疫反应的功能 关于肠道内环境的平衡。新型T细胞的综合表型和功能特征 缺乏母乳抗体的新生儿产生的依赖免疫反应将提供关键的机制 关于母乳喂养如何有助于长期健康的见解。这里概述的研究将奠定基础 用于开发干预和治疗，以操纵宿主与微生物区系的关系，以及 促进长期健康，特别是对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.