Department of Immunology, Harvard Medical School, Boston MA 02115, USA.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Immunity. 2021 Mar 9;54(3):499-513.e5. doi: 10.1016/j.immuni.2021.02.002.
The immune and enteric nervous (ENS) systems monitor the frontier with commensal and pathogenic microbes in the colon. We investigated whether FoxP3 regulatory T (Treg) cells functionally interact with the ENS. Indeed, microbe-responsive RORγ and Helios subsets localized in close apposition to nitrergic and peptidergic nerve fibers in the colon lamina propria (LP). Enteric neurons inhibited in vitro Treg (iTreg) differentiation in a cell-contact-independent manner. A screen of neuron-secreted factors revealed a role for interleukin-6 (IL-6) in modulating iTreg formation and their RORγ proportion. Colonization of germfree mice with commensals, especially RORγ Treg inducers, broadly diminished colon neuronal density. Closing the triangle, conditional ablation of IL-6 in neurons increased total Treg cells but decreased the RORγ subset, as did depletion of two ENS neurotransmitters. Our findings suggest a regulatory circuit wherein microbial signals condition neuronal density and activation, thus tuning Treg cell generation and immunological tolerance in the gut.
免疫系统和肠神经系统（ENS）监测结肠中共生菌和病原菌的前沿。我们研究了 FoxP3 调节性 T（Treg）细胞是否与 ENS 具有功能相互作用。事实上，微生物反应性 RORγ 和 Helios 亚群定位于结肠固有层（LP）中的氮能和肽能神经纤维附近。肠神经元以非细胞接触方式抑制体外 Treg（iTreg）分化。对神经元分泌因子的筛选表明，白细胞介素 6（IL-6）在调节 iTreg 形成及其 RORγ 比例中起作用。共生菌定植于无菌小鼠，特别是 RORγ Treg 诱导剂，广泛减少结肠神经元密度。形成闭环，神经元中 IL-6 的条件性缺失增加了总 Treg 细胞，但减少了 RORγ 亚群，如两种 ENS 神经递质的耗竭也是如此。我们的发现表明存在一个调节回路，其中微生物信号调节神经元密度和激活，从而调节肠道中 Treg 细胞的生成和免疫耐受。
