Editors' ChoiceImmunology

Glucocorticoids and PD-1

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Science Signaling  04 Sep 2018:
Vol. 11, Issue 546, eaav2683
DOI: 10.1126/scisignal.aav2683

Signaling by the glucocorticoid receptor in NK cells induces expression of the checkpoint inhibitor PD-1 to prevent immunopathology.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis stimulates the synthesis and release of glucocorticoids, such as cortisol, from the adrenal cortex into the blood. These factors then activate cytosolic receptors in target cells to induce target gene expression. The HPA axis is activated in response to systemic inflammation and during viral infection and is required to resolve inflammation and restore homeostasis. To better define the mechanisms by which glucocorticoids modulate immune responses, Quatrini et al. knocked out the glucocorticoid receptor (GR) mostly in natural killer (NK) cells in mice and examined the effects on infection by the virus MCMV. After MCMV infection, endogenous glucocorticoids increased the cell surface abundance of the checkpoint inhibitor programmed cell death 1 (PD-1) on wild-type, but not GR-deficient, NK cells in the spleen, but not the liver. In vitro studies showed that the cytokine interleukin-15 (IL-15), which was abundant in the spleen, acted with glucocorticoid to induce PD-1 expression, whereas IL-12, which was more abundant than IL-15 in the liver, inhibited this process. The increased cell surface abundance of PD-1 on NK cells was associated with decreased production of the cytokine interferon-γ (IFN-γ), but had no effect on viral clearance, suggesting that the cytolytic (direct killing) functions of GR-deficient and wild-type NK cells were similar. However, a consequence of the reduced production of IFN-γ was a decrease in inflammation and immunopathology in the spleen. As Biron discusses in a commentary, these data suggest that the HPA axis, through the induction of PD-1 on NK cells, protects against cytokine-mediated damage during viral infection.

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