Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

The innate immune system plays essential roles in brain development, including the remodeling of neuronal synapses. Innate lymphocytes are the most recently discovered member of the innate immune arsenal, whose developmental expansion and activation make them potential mediators of brain-immune communication during synapse formation. Here we show that group 2 innate lymphoid cells (ILC2s) and their cytokine Interleukin-13 (IL-13) signal directly to inhibitory interneurons to increase inhibitory synapse density in the developing brain. ILC2s expanded and produced IL-13 in the developing brain meninges. Loss of ILC2s or IL-13 signaling to interneurons decreased inhibitory, but not excitatory, cortical synapses. Conversely, ILC2s and IL-13 were sufficient to increase inhibitory synapses. Loss of this signaling pathway led to selective impairments in social interaction. These data define a type 2 neuroimmune circuit in early life that shapes inhibitory synapse development and behavior. Comparison between IL-33-/- mice and IL-33+/- mice to address the role of IL-33 signaling in dural meninges at postnatal day 14.先天免疫系统（innate immune system）在大脑发育过程中发挥核心作用，涵盖神经元突触的重塑过程。先天淋巴细胞（innate lymphocytes）是近年新发现的先天免疫库成员，其发育扩增与激活特性使其成为突触形成阶段脑-免疫交流的潜在介导因子。本研究证实，2型先天淋巴细胞（group 2 innate lymphoid cells，ILC2s）及其分泌的细胞因子白细胞介素-13（Interleukin-13，IL-13）可直接作用于抑制性中间神经元，提升发育中大脑内的抑制性突触密度。ILC2s在发育中大脑的脑膜中发生扩增并分泌IL-13。缺失ILC2s或阻断IL-13向中间神经元的信号传递，会降低皮层的抑制性突触数量，但不会影响兴奋性突触。反之，补充ILC2s或IL-13即可有效提升抑制性突触密度。该信号通路的缺失会导致社交互动出现选择性损伤。本研究数据明确了生命早期存在一条2型神经免疫环路，该环路可调控抑制性突触的发育与个体行为表现。本研究还对比了IL-33基因敲除小鼠（IL-33-/-）与IL-33杂合子小鼠（IL-33+/-），以探究IL-33信号在出生后第14天硬脑膜中的作用。