b-Adrenergic receptor (b-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, bAR expression on immune cells affects their ability to mount antitumor immune responses. However, how bAR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective b-blocker, strongly improved the efficacy of an antitumor STxBE7 vaccine by enhancing the frequency of CD8 þ T lymphocytes infiltrating the tumor (TIL). However, propranolol had no effect on the reactivity of CD8 þ TILs, a result further strengthened by ex vivo experiments showing that these cells were insensitive to adrenaline-or noradrenaline-induced AR signaling. In contrast, na€ ve CD8 þ T-cell activation was strongly inhibited by bAR signaling, and the beneficial effect of propranolol mainly occurred during CD8 þ T-cell priming in the tumor-draining lymph node. We also demonstrated that the differential sensitivity of na€ ve CD8 þ T cells and CD8 þ TILs to bAR signaling was linked to a strong downregulation of b 2-AR expression related to their activation status, since in vitro-activated CD8 þ T cells behaved similarly to CD8 þ TILs. These results revealed that bAR signaling suppresses the initial priming phase of antitumor CD8 þ T-cell responses, providing a rationale to use clinically available b-blockers in patients to improve cancer immunotherapies.

Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav1.8+ sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav1.8-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav1.8+ sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.