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 to mouse cytomegalovirus infection. Mechanistically, endogenous glucocorticoids produced shortly after infection induced the selective and tissue-specific expression of the checkpoint molecule PD-1 on NK cells. This glucocorticoid–PD-1 pathway limited the production of the cytokine interferon-γ (IFN-γ) by splenic NK cells, which prevented lethal immunopathology. Importantly, 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.