Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms.

免疫系统失调是阿片类药物成瘾的主要特征。在这里，我们描述了阿片类药物使用障碍患者和健康对照者外周免疫细胞的特征。阿片类药物相关的血液表现出免疫细胞的异常分布，其特征是脆弱样调节性 T 细胞 (Tregs) 显着扩张，这与戒断评分呈正相关。类似地，阿片类药物治疗的小鼠也表现出增强的 Treg 衍生干扰素-γ (IFN-γ) 表达。IFN-γ 信号重塑伏隔核 (NAc) 神经元的突触形态，调节随后的戒断症状。我们证明阿片类药物通过下调星形胶质细胞衍生的脂肪酸结合蛋白 7 (Fabp7) 来增加神经元衍生的 CC 基序趋化因子配体 2 (Ccl2) 的表达和破坏血脑屏障 (BBB) 的完整性，这两者都会触发外周 Treg 浸润到 NAc 中。我们的研究表明，阿片类药物驱动脆弱样 Tregs 的扩张，并有利于 BBB 的外周 Treg 渗出，这导致 IFN-γ 介导的突触不稳定和随后的戒断症状。