Sympathetic nervous tone influences the development and function of natural killer cells

Abstract

Signals derived from the nervous system inform immune development and function in a variety of ways. For example, sympathetic nervous system (SNS) activity has been demonstrated to influence the function of innate lymphoid cells (ILCs) in the context of inflammation. Natural killer (NK) cells, a subset of ILCs, are important players in the anti-tumor immune response that possess the capability to respond to signals from the SNS via expression of adrenergic receptors (ARs) on their surface. Given the critical functions of NK cells in tumor immunity and their capacity to respond to SNS signals, we hypothesized that SNS input plays a key regulatory role in the NK-mediated anti-tumor response. Here, we demonstrate that the SNS delivers a critical maturation signal that promotes NK cell development and influences their cytotoxic capacity. Mice that lack functional SNS signaling after peripheral administration of 6-hydroxydopamine exhibit a higher proportion of poorly cytotoxic NK2 cells (CD11b⁻CD27⁺) and a lower proportion of potently cytotoxic NK1 cells (CD11b⁺CD27⁻) compared to controls. Furthermore, analysis of single-cell RNA sequencing establishes that SNS ablation disrupts normal NK development and that immature NK cells accumulate in SNS-ablated tumor-bearing mice. Together, these data demonstrate that tonic sympathetic nervous activity plays an important role in NK development. Further characterization of this role will improve our understanding of the consequences of neuroimmune interactions in cancer and inform the development of cancer immunotherapy.