Meningeal immunity - a middleman between gut microbiome and the brain

修改项目摘要/摘要部分 外周T细胞功能障碍与学习障碍、社会行为改变和神经发生减少有关。用来自野生型供体的T细胞重建免疫缺陷受体可以恢复这些脑功能。T细胞通过脑膜间隙介导其对大脑的有益作用，这与通过脑膜淋巴管的外周免疫密切相关。研究还表明，慢性应激与肠道炎症以及学习和神经发生障碍有关。我们已经解决了，至少部分，什么类型的免疫细胞介导的神经免疫相互作用（T细胞），在哪里（脑膜空间），虽然外周免疫的变化作为压力的结果是如何影响大脑尚未得到解决。基于我们的新数据，我们的目标是为这些复杂的相互作用提供新的见解。我们的总体假设是，由于压力导致的肠道微生物群的变化促进了颈深淋巴结免疫组成的变化，这反映在脑膜免疫中，这反过来又影响了大脑功能，从而形成了一个三方循环：大脑-免疫-肠道。 在这项提案中，我们将讨论犬尿氨酸途径的代谢物如何影响脑膜间隙中的T细胞功能，以及这些免疫变化如何影响脑功能，犬尿氨酸途径在肠道微生物组的慢性轻度应激期间被发现失调。我们的研究结果表明，肠道微生物群可以作为治疗目标，以减轻慢性应激期间的异常免疫变化，从而保护大脑。

Modified Project Summary/Abstract Section Malfunction of peripheral T cells is associated with impaired learning, changes in social behaviors and reduced neurogenesis. Reconstitution of immune deficient recipients with T cells from wild type donors restores these brain functions. T cells mediate their beneficial effects on the brain through meningeal spaces, which are closely associated with peripheral immunity through the meningeal lymphatic vessels. It has also been demonstrated that chronic stress is correlated with gut inflammation and with impairments in learning and neurogenesis. We have addressed, at least partially, what type of immune cells are mediating neuro-immune interactions (T cells), and where (meningeal spaces), although how the changes in peripheral immunity as a result of stress are impacting the brain has not yet been addressed. Based on our new data, we aim to provide novel insights into these complex interactions. Our overarching hypothesis is that changes in the gut microbiota as a result of stress facilitate changes in the immune composition of the deep cervical lymph nodes, which are reflected in meningeal immunity, which in turn impacts brain function, thus creating a tripartite loop: brain-immune-gut. In this proposal, we will address how metabolites of the kynurenine pathway, found to be dysregulated during chronic mild stress by the gut microbiome, affect T cell function in the meningeal spaces, and how these immune changes impact brain function. Our results suggest that gut microbiota could be targeted therapeutically to mitigate abnormal immune changes during chronic stress, which in turn would protect the brain.