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

Abstract

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.

Neuroendocrine regulation of innate lymphoid cells

“…PD‐1 is an immune checkpoint involved, in particular, in the downregulation of T‐cell activity. We showed that the GR‐PD‐1 pathway plays a major role in NK cells, regulating their IFN‐γ production in the spleen and promoting host resistance to infection . This regulatory mechanism is essential to prevent IFN‐γ‐dependent spleen immunopathology but does not affect the local control of viral replication (Figure ).…”

“…However, the mechanisms underlying this inhibition were unclear, as many hematopoietic and non‐hematopoietic cells express the GR. We showed in GR Ncr1 ‐iCre mice that, as observed after LPS injection, endogenous GCs produced in response to MCMV infection prevent excessive IFN‐γ production by NK cells in the spleen . However, this regulation was organ‐specific as the disruption of GC responsiveness in liver NCR1 + ILCs (ie, NK cells and ILC1) did not affect their IFN‐γ production.…”

“…The organ‐specific mechanism by which GR regulates gene expression may depend on the different cytokine environments of the spleen and liver (Figure ). Consistent with this hypothesis, we showed that PD‐1 expression on NK cells in vitro is induced by simultaneous stimulation with IL‐15, IL‐18, and corticosterone, whereas the addition of IL‐12 abolishes this effect …”

“…Analysis of the genes regulated by GR in liver ILC 1s upon MCMV infection. Transcriptomic data ( RNA seq) published in are analyzed ( GSE 114827) . The differentially expressed genes ( DEG s) between liver ILC 1s sorted from MCMV infected Control and GR Ncr1 ‐iCre mice were classified into non‐redundant functional categories by combining gene ontology ( GO ) analysis and literature‐based manual curation (A).…”

“…In the liver of MCMV‐infected mice, the GR‐dependent control of gene expression is very different in NK cells and ILC1s. Only two genes are modulated by this pathway in NK cells, whereas the transcription of 130 genes is GR‐dependent in ILC1s (Figure ) . Many of these genes are involved in immune cell processes, including adhesion and migration (Figure ).…”