Meningeal immunity - a middleman between gut microbiome and the brain

 描述(由申请人提供)：我们已经证明外周T细胞的缺乏或功能障碍与学习障碍和异常的神经发生有关。此外，我们还揭示了这些缺陷可以通过用野生型供者的T细胞重建免疫缺陷的受体来修复。我们发现，在有益于大脑功能的神经免疫相互作用中，巡逻脑膜的T细胞是核心角色。它还被广泛证明，慢性应激与肠道炎症以及学习和神经发生的损害有关。我们已经解决了，至少部分地，什么类型的免疫细胞在介导神经免疫相互作用(T细胞)，以及在哪里(脑膜间隙)，尽管压力导致的外周免疫的变化如何影响大脑还没有解决。在这里，我们的目标是为这些复杂的相互作用提供新的见解。我们的主要假设是，压力导致的肠道微生物区系的变化促进了脑膜免疫系统的变化，而脑膜免疫系统反过来又影响了大脑功能，从而形成了一个三部环-大脑、免疫和肠道。在探索R21阶段，我们计划通过以下内容来表征慢性应激下肠道微生物区系和脑膜免疫细胞之间的相互作用：(1)由于慢性应激期间微生物群的变化而导致的脑膜T细胞的表型变化；(2)免疫系统与迷走神经对脑膜T细胞表型变化的贡献；以及(3)由于慢性应激期间微生物区系的变化而导致的血液代谢物的分子特征。这一阶段的成功完成将确定肠道微生物区系和大脑之间通过免疫系统、迷走神经刺激和/或微生物代谢物之间的潜在机制联系。在第二个假设驱动阶段，我们将测试Th2细胞缺陷是否与抑郁症有关。据我们所知，这是第一次尝试将 肠道微生物区系通过一种明确的中介细胞类型影响大脑功能。我们期望肠道微生物区系通过脑膜T细胞产生IL-4来支持脑功能和神经发生(直接的，或通过额外的细胞介质)。

 DESCRIPTION (provided by applicant): We have demonstrated that lack or dysfunction of peripheral T cells is associated with impaired learning and aberrant neurogenesis. Moreover, we have revealed that these deficits can be remedied by reconstitution of immune deficient recipients with T cells from wild type donors. We showed that the T cells that patrol the meninges of the brain are central players in neuroimmune interactions that benefit brain function. It has also been widely 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 is 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 been addressed. Here we aim to provide new insights into these complex interactions. Our overarching hypothesis is that changes in the gut microbiota as a result of stress facilitate changes in the meningeal immune system, which in turn impacts brain function, thus creating a tripartite loop - brain, immune and gut. During the exploratory R21 phase we plan to characterize the interactions between the gut microbiota and meningeal immune cells under chronic stress, by addressing: (1) the phenotype change of meningeal T cells as a result of microbiome alterations during chronic stress; (2) contributions of the immune system vs. vagus nerve to changes in meningeal T cell phenotype; and (3) the molecular signature of blood metabolites as a result of microbiota changes during chronic stress. Successful completion of this phase will determine the underlying mechanistic link between the gut microbiota and the brain via the immune system, vagus nerve stimulation, and/or microbial metabolites. In the second, hypothesis-driven phase, we will test if a defect in Th2 cells is associated with depression. To our knowledge, this is the first attempt to mechanistically link the gut microbiota to brain function by a defined mediating cell type. We expect the gut microbiota to mediate IL-4 production by meningeal T cells in support of brain function and neurogenesis (directly, or via additional cellular mediators).