Meningeal gd T cells regulate anxiety like behaviors via Il17a signaling on Neurons (PFC neurons). Meningeal gd T cells regulate anxiety like behaviors via Il17a signaling on Neurons (PFC neurons)

Interleukin 17a (IL-17a) is a cytokine that has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Recent studies in mouse models of maternal immune activation suggest that IL-17a is also linked to behavioral changes reminiscent of those seen under pathological conditions such as autism spectrum disorders (ASD)1 and in aggregation behavior in Caenorhabditis elegans2, raising the intriguing possibility that this cytokine might have evolved for the homeostatic regulation of neuronal activity. Here, by in-depth cellular and molecular characterization of a unique population of meningeal-resident gd17 T cells, we characterized the nearest central nervous system (CNS)-associated source of IL-17a under homeostasis. Meningeal gd T cell-derived IL-17a was associated with anxiety-like behaviors in mice, which partially depended on T-cell receptor engagement and commensal microbiota. IL-17a receptor was highly expressed in glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice by shaping the transcriptional landscape and synaptic transmission of neurons in the medial prefrontal cortex (mPFC). From an evolutionary perspective, these findings suggest that IL-17a production by tissue-resident meningeal gd17 T cells may represent an evolutionary bridge between conserved anti-pathogen molecules and avoidance/survival behavioral traits in vertebrates. Overall design: 3 nuclei samples of 4 mice pooled after elevated plus maze task from SynCre:Il17rafl/fl, SynCre, and Il17ra fl/fl mice.

白细胞介素17a（Interleukin 17a, IL-17a）是一类在脊椎动物免疫系统（vertebrate immune system）演化过程中高度保守的细胞因子（cytokine），在感染与自身免疫相关研究中被广泛探讨。近期针对母体免疫激活（maternal immune activation）小鼠模型的研究显示，IL-17a还与多种病理状态下的行为改变相关——例如自闭症谱系障碍（Autism Spectrum Disorders, ASD）患者的行为特征，以及秀丽隐杆线虫（Caenorhabditis elegans）的聚集行为，这引出了一个引人深思的假说：该细胞因子或许演化而来的功能是稳态调控（homeostatic regulation）神经元活动（neuronal activity）。本研究通过对一类独特的脑膜驻留型gd17 T细胞（meningeal-resident gd17 T cells）进行深入的细胞与分子表征，明确了稳态条件下中枢神经系统（Central Nervous System, CNS）周边最接近的IL-17a来源。研究发现，脑膜gd T细胞分泌的IL-17a与小鼠的焦虑样行为（anxiety-like behaviors）相关，该关联部分依赖于T细胞受体结合（T-cell receptor engagement）与共生菌群（commensal microbiota）的调控。静息状态（steady state）下，谷氨酸能神经元（glutamatergic neurons）高表达IL-17a受体；对该受体进行基因敲除（genetic deletion）后，可通过重塑内侧前额叶皮层（Medial Prefrontal Cortex, mPFC）内神经元的转录组谱（transcriptional landscape）与突触传递（synaptic transmission）功能，降低小鼠的焦虑样行为。从演化视角来看，上述研究结果提示，组织驻留型（tissue-resident）脑膜gd17 T细胞产生的IL-17a，可能是脊椎动物中保守的抗病原体分子与规避/生存行为特征之间的演化桥梁。整体实验设计：选取SynCre:Il17rafl/fl、SynCre及Il17ra fl/fl三种基因型小鼠，在完成高架十字迷宫任务（elevated plus maze task）后，将4只小鼠的脑组织样本混合后提取细胞核，共制备3份此类细胞核样本。