Research ArticleMYELOID CELLS

Sympathetic nervous tone limits the development of myeloid-derived suppressor cells

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Science Immunology  11 Sep 2020:
Vol. 5, Issue 51, eaay9368
DOI: 10.1126/sciimmunol.aay9368

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A sympathetic tumor response

The sympathetic nervous system (SNS) has been shown to regulate immune responses through various mechanisms. Nevin et al. now show that ablation of SNS signaling can suppress tumor immunity, and this is caused by disruption in α-adrenergic signaling that is needed for myeloid cell maturation. In tumor-bearing mice, this disruption promotes the accumulation of immature myeloid-derived suppressor cells, which allows for tumor growth. In the absence of intact SNS signaling, MDSCs also promote expansion of regulatory T cells by secreting the alarmin heterodimer S100A8/A9. These results provide insight into the contributions of SNS signaling in innate and adaptive immunity, particularly in the context of tumor immunity.

Abstract

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.

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