ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Immunol. 2018; 19(9): 954–962.

The immune system protects the host organism against infectious diseases, however, pathogen elimination frequently entails collateral tissue damage and inflammation, which decrease host fitness (1). Neuroendocrine-immune interactions play an important role in these regulatory processes (2, 3). Endogenous glucocorticoids (cortisol in humans and corticosterone in rodents) regulate many physiological and developmental processes through their ubiquitously expressed glucocorticoid receptor (GR). The HPA neuro-endocrine pathway restores homeostasis by limiting and resolving inflammation in many conditions (2). The HPA axis is activated during infection with viruses, such as influenza 10 and cytomegalovirus (CMV) (4). Murine CMV (MCMV) is a beta herpesvirus used as a model for systemic human CMV infection, which can cause severe disease, especially in immunocompromised patients. Mice rendered glucocorticoid-deficient by adrenalectomy are more susceptible to MCMV-induced death, due to the deleterious effects of cytokine-induced over-inflammation, and resistance is restored by corticosterone replacement (5). In all these conditions, the underlying mechanisms of glucocorticoids remain unclear, because GRs are expressed by many hematopoietic and non-hematopoietic cells and can impact on multiple signaling pathways. During acute infection, the cytokine interferon-γ (IFN-γ), produced by innate lymphoid cells (ILCs) is essential for antiviral defense. These IFN-γ-producing ILCs include spleen and liver natural killer (NK) cells and liver ILC1s, which all express the GR (6).

In this study, the authors investigated the role of the GR in ILC subsets relevant to MCMV infection. They used mice with a conditional deletion of the GR gene in ILCs expressing NK cells, ILC1s and a subset of ILC3s. They found that endogenous glucocorticoids produced rapidly after infection induced the selective and tissue-specific expression of the immune checkpoint PD-1 on the surface of spleen NK cells. Concomitantly, PD-1 ligands were upregulated in several immune cell subsets. PD-1 signalling was required for host survival to infection and acted by limiting the production of IFN-γ by NK in the spleen, which prevented immunopathology. This neuroendocrine-immune axis controlled immune tolerance but did not impair viral clearance.

The glucocorticoid-dependent induction of PD-1 expression on NK cells in MCMV infection is a previously unrecognized mechanism by which the HPA axis suppresses immunopathology and promotes autoimmune disease resistance without compromising protective immunity. Therefore, these findings demonstrate a major role for the HPA axis in promoting host resistance to an infectious disease through regulation of the PD-1 inhibitory pathway in an ILC subset. A deeper understanding of the physiological and pathological conditions in which this glucocorticoid-PD-1 pathway exerts some beneficial or detrimental effects could provide a rational basis for the development of new therapeutic strategies.

References: 1. Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science. 2012; 335:936–941.

2. Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol. 2002; 20:125–163.

3. Irwin MR, Cole SW. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol. 2011; 11:625–632.

4. Ruzek MC, Miller AH, Opal SM, Pearce BD, Biron CA. Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection. J Exp Med. 1997; 185:1185–1192.

5. Ruzek MC, Pearce BD, Miller AH, Biron CA. Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection. J Immunol. 1999; 162:3527–3533.

6. Quatrini L, et al. Host resistance to endotoxic shock requires the neuroendocrine regulation of group 1 innate lymphoid cells. J Exp Med. 2017; 214(12): 3531–3541.