The connection between the nervous and immune systems is increasingly recognized as crucial for health and disease. Specifically, the sympathetic nervous system (SNS) has been shown to strongly impact immune responses. SNS fibers innervate all tissues and release the catecholamine noradrenaline locally. Highly diverse cell types respond to noradrenaline through cell surface G-protein coupled a- or b-adrenergic receptors (ARs). The skin represents one of the first lines of defense of an organism against pathogens and it is densely innervated by SNS fibers. It harbors numerous immune cells, among which we find dendritic cells (DCs), that act as sentinels, reacting to pathogens or malignant cell proliferation by mounting a robust inflammatory response and inducing the recruitment of additional immune cells. The migration of DCs through the lymphatic vessels network is crucial to achieve an efficient adaptive immune response. The SNS has been shown to govern immune cell trafficking and the inflammatory response in several peripheral tissues, such as lymph node as well as skeletal muscle, bone marrow and blood. This study investigated how the SNS governs DC trafficking within the skin.

Here, I demonstrated that noradrenergic signaling via b2-AR, the primary receptor for norepinephrine on immune cells, regulates DCs migration towards both skin LVs and skin draining lymph nodes (dLNs). Specifically, mice lacking b2-AR (b2KO), showed increased DC migration towards lymphatic vessels compared to WT mice ex vivo. This phenotype was confirmed via pharmacological inhibition using the specific b2-AR antagonist clenbuterol. Adoptive transfer of bone marrow derived dendritic cells (BMDCs) in the skin showed that the main player involved in this phenomenon in vivo are DCs, as b2KO BMDCs had an advantage in the migration towards skin dLNs, regardless of the genotype of the recipient.

This enhanced migration in b2KO DCs also impacted tumor responses, due to the central role of DCs in orchestrating effective CD8+T cell responses against tumors. B16-OVA melanoma tumor bearing mice vaccinated with b2KO BMDCs, showed a stronger anti-tumor immune response compared to mice vaccinated with WT BMDCs. Importantly, single-cell RNA sequencing analysis of mouse skin revealed that cDC1s are the DCs subpopulation which expresses the highest levels of the b2-AR. Vaccinating B16-OVA melanoma tumor bearing mice with cDC1s lacking noradrenergic signaling (either b2KO cDC1s or WT cDC1s pre-conditioned with the specific b2-AR antagonist ICI.118.551), resulted in a significantly better tumor control, VIIIcompared to control mice. One of the factors driving this effect could be the proximity observed between XCR1+ cDC1s and TH+ sympathetic nerves in the skin.

This study sheds light on how the SNS modulates the immune system and this may lead to the pharmacological optimization of vaccination regimes, as well as anti-tumor therapies.