Nociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection.

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.

ß2-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection.

In humans, psychological stress has been associated with a higher risk of infectious illness. However, the mechanisms by which the stress pathway interferes with host response to pathogens remain unclear. We demonstrate here a role for the ß2-adrenergic receptor (ß2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection. Mice treated with a ß2-AR agonist were more susceptible to MCMV infection. By contrast, ß2-AR deficiency resulted in a better clearance of the virus, less tissue damage, and greater resistance to MCMV. Mechanistically, we found a correlation between higher levels of IFN-γ production by liver natural killer (NK) cells and stronger resistance to MCMV. However, the control of NK cell IFN-γ production was not cell intrinsic, revealing a cell-extrinsic downregulation of the antiviral NK cell response by adrenergic neuroendocrine signals. This pathway reduces host immune defense, suggesting that the blockade of the ß2-AR signaling could be used to increase resistance to infectious diseases.

Blockade of ß-Adrenergic Receptors Improves CD8+ T-cell Priming and Cancer Vaccine Efficacy.

ß-Adrenergic receptor (ß-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, ß-AR expression on immune cells affects their ability to mount antitumor immune responses. However, how ß-AR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective ß-blocker, strongly improved the efficacy of an antitumor STxBE7 vaccine by enhancing the frequency of CD8+ T lymphocytes infiltrating the tumor (TIL). However, propranolol had no effect on the reactivity of CD8+ TILs, a result further strengthened by ex vivo experiments showing that these cells were insensitive to adrenaline- or noradrenaline-induced AR signaling. In contrast, naïve CD8+ T-cell activation was strongly inhibited by ß-AR signaling, and the beneficial effect of propranolol mainly occurred during CD8+ T-cell priming in the tumor-draining lymph node. We also demonstrated that the differential sensitivity of naïve CD8+ T cells and CD8+ TILs to ß-AR signaling was linked to a strong downregulation of ß2-AR expression related to their activation status, since in vitro-activated CD8+ T cells behaved similarly to CD8+ TILs. These results revealed that ß-AR signaling suppresses the initial priming phase of antitumor CD8+ T-cell responses, providing a rationale to use clinically available ß-blockers in patients to improve cancer immunotherapies.

Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells.

Controlling the balance between immunity and immunopathology is crucial for host resistance to pathogens. After infection, activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to the production of glucocorticoids. However, the pleiotropic effects of these steroid hormones make it difficult to delineate their precise role(s) in vivo. Here we found that the regulation of natural killer (NK) cell function by the glucocorticoid receptor (GR) was required for host survival after infection with mouse cytomegalovirus (MCMV). Mechanistically, endogenous glucocorticoids produced shortly after infection induced selective and tissue-specific expression of the checkpoint receptor PD-1 on NK cells. This glucocorticoid-PD-1 pathway limited production of the cytokine IFN-γ by spleen NK cells, which prevented immunopathology. Notably, this regulation did not compromise viral clearance. Thus, the fine tuning of NK cell functions by the HPA axis preserved tissue integrity without impairing pathogen elimination, which reveals a novel aspect of neuroimmune regulation.

Host resistance to endotoxic shock requires the neuroendocrine regulation of group 1 innate lymphoid cells.

Upon infection, the immune system produces inflammatory mediators important for pathogen clearance. However, inflammation can also have deleterious effect on the host and is tightly regulated. Immune system-derived cytokines stimulate the hypothalamic-pituitary-adrenal (HPA) axis, triggering endogenous glucocorticoid production. Through interaction with ubiquitously expressed glucocorticoid receptors (GRs), this steroid hormone has pleiotropic effects on many cell types. Using a genetic mouse model in which the gene encoding the GR is selectively deleted in NKp46+ innate lymphoid cells (ILCs), we demonstrated a major role for the HPA pathway in host resistance to endotoxin-induced septic shock. GR expression in group 1 ILCs is required to limit their IFN-γ production, thereby allowing the development of IL-10-dependent tolerance to endotoxin. These findings suggest that neuroendocrine axes are crucial for tolerization of the innate immune system to microbial endotoxin exposure through direct corticosterone-mediated effects on NKp46-expressing innate cells, revealing a novel strategy of host protection from immunopathology.

Resistance for Genotoxic Damage in Mesenchymal Stromal Cells Is Increased by Hypoxia but Not Generally Dependent on p53-Regulated Cell Cycle Arrest.

Adult stem cells including multipotent mesenchymal stromal cells (MSC) acquire a high amount of DNA-damage due to their prolonged lifespan. MSC may exert specific mechanisms of resistance to avoid loss of functional activity. We have previously shown that resistance of MSC is associated with an induction of p53 and proliferation arrest upon genotoxic damage. Hypoxia may also contribute to resistance in MSC due to the low oxygen tension in the niche. In this study we characterized the role of p53 and contribution of hypoxia in resistance of MSC to genotoxic damage. MSC exhibited increased resistance to cisplatin induced DNA-damage. This resistance was associated with a temporary G2/M cell cycle arrest, induction of p53- and p21-expression and reduced cyclin B / cdk1-levels upon subapoptotic damage. Resistance of MSC to cisplatin was increased at hypoxic conditions i. e. oxygen <0.5%. However, upon hypoxia the cisplatin-induced cell cycle arrest and expression of p53 and p21 were abrogated. MSC with shRNA-mediated p53 knock-down showed a reduced cell cycle arrest and increased cyclin B / cdk1 expression. However, this functional p53 knock down did not alter the resistance to cisplatin. In contrast to cisplatin, functional p53-knock-down increased the resistance of MSC to etoposide. We conclude that resistance of MSC to genotoxic damage is influenced by oxygen tension but is not generally dependent on p53. Thus, p53-dependent and p53-independent mechanisms of resistance are likely to contribute to the life-long functional activity of MSC in vivo. These findings indicate that hypoxia and different resistance pathways contribute to the phenotype that enables the prolonged lifespan of MSC.

Complementarity and redundancy of IL-22-producing innate lymphoid cells.

Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet-dependent differentiation of NCR(-) ILC3 cells into NCR(+) ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR(+) ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR(+) ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis.