Sympathetic nerves that innervate lymphoid organs regulate immune development and function by releasing norepinephrine that is sensed by immune cells via their expression of adrenergic receptors. Here, we demonstrate that ablation of sympathetic nervous system (SNS) signaling suppresses tumor immunity, and we dissect the mechanism of such immune suppression. We report that disruption of the SNS in mice removes a critical α-adrenergic signal required for maturation of myeloid cells in normal and tumor-bearing mice. In tumor-bearing mice, disruption of the α-adrenergic signal leads to the accumulation of immature myeloid-derived suppressor cells (MDSCs) that suppress tumor immunity and promote tumor growth. Furthermore, we show that these SNS-responsive MDSCs drive expansion of regulatory T cells via secretion of the alarmin heterodimer S100A8/A9, thereby compounding their immunosuppressive activity. Our results describe a regulatory framework in which sympathetic tone controls the development of innate and adaptive immune cells and influences their activity in health and disease.

支配淋巴器官的交感神经通过释放去甲肾上腺素来调节免疫发育和功能，而去甲肾上腺素是由免疫细胞通过其肾上腺素能受体的表达来感知的。在这里，我们证明了交感神经系统 (SNS) 信号的消融抑制了肿瘤免疫，我们剖析了这种免疫抑制的机制。我们报告说，小鼠 SNS 的破坏消除了正常和荷瘤小鼠骨髓细胞成熟所需的关键 α-肾上腺素能信号。在荷瘤小鼠中，α-肾上腺素能信号的破坏会导致未成熟髓源性抑制细胞 (MDSC) 的积累，从而抑制肿瘤免疫并促进肿瘤生长。此外，我们表明这些 SNS 响应性 MDSC 通过分泌警报素异二聚体 S100A8/A9 来驱动调节性 T 细胞的扩增，从而增加它们的免疫抑制活性。我们的研究结果描述了一个调节框架，其中交感神经张力控制先天和适应性免疫细胞的发育，并影响它们在健康和疾病中的活动。