Sympathetic nervous system-mediated β-adrenergic signaling maintains the pool of mature natural killer cells

Abstract

Abstract The sympathetic nervous system (SNS) innervates all lymphoid tissues and is, thus, well-positioned to influence the activity of immune cells. Accordingly, the coordinated responses of the SNS and immune system are crucial for immune responses to infection and cancer. Natural killer (NK) cells are essential for the immune response to certain viral infections and cancers in which they kill infected or cancerous cells and produce cytokines and chemokines to instruct the activity of other cells contributing to the response. We find here that steady state SNS signaling maintains the balance of mature and immature NK cells in the spleen and bone marrow. Using 6-hydroxydopamine to ablate sympathetic nerve terminals, we show by single cell RNA-sequencing and flow cytometry that SNS-ablated mice have decreased frequencies of mature CD27− CD11b+ NK cells and increased frequencies of immature CD27+ CD11b− and intermediate CD27+ CD11b+ NK cells. An increased ratio of immature NK cells to mature NK cells has been linked to decreased anti-tumor immunity. Along these lines, SNS-ablation also increases the growth rate of RMA-S tumors, the rejection of which depends on NK cells. This accelerated tumor growth was dependent on the absence of both α- and β-adrenergic signaling. Culture of early NK cell precursors in the presence of selective α- or β-adrenergic agonists suggests that signaling through β-adrenergic receptors promotes the maturation of NK cells. These data suggest that signaling through β-adrenergic receptors mediated by norepinephrine produced by the SNS maintains the pool of mature NK cells, allowing them to effectively survey peripheral tissues and participate in anti-tumor immunity.