A study published in the Journal of Immunology demonstrates that estrogens may boost innate immunity by enhancing interferon (IFN)-γ production by CD11c(+) dendritic cells.
In humans, the sex differences or the sexual dimorphism in immune defense is a well-known phenomenon. Females have more vigorous cellular and humoral immune responses, and they are more resistant to infections – the prevalence and intensity of viral, bacterial, and parasitic infections are typically reduced in females compared with males.
Sex hormones such as estrogens directly affect immunity and estrogen receptors are expressed on circulating lymphocytes, dendritic cells (DCs), NK cells, and macrophages. Previous research indicates that estrogens are able to facilitate the production of IFN-γ by NK cells.
Estrogens are lipophilic hormones that exert their biological effects by binding to intracellular receptors, specifically estrogen receptor (ER) α and ERβ. Both receptor subtypes are present in the thymus and spleen as well as in circulating lymphocytes, dendritic cells(DCs), NK cells, and macrophages.
In the Journal of Immunology study, Mark Siracusa and colleagues from the Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA demonstrate that 17β-estradiol (E2) promoted the differentiation of bone marrow precursor cells into functional CD11c+CD11b+MHC class II+ DCs.
Importantly, the authors found that CD11c+ splenocytes isolated from animals with supplemental E2 produced more IFN-γ in response to IL-12 and IL-18. Of note, preceding work shows that CD11c(+)NK1.1(+) cells are a significant source of IFN-γ production, and this IFN-γ is vital for the protection against intracellular infections.
In the Journal of Immunology study, only bone marrow-derived dendritic cells (BMDCs) matured in the presence of E2 were responsive to LPS, CpG, and, to a lesser extent poly I:C, in which the expression of MHCII, CD40, and CD86 as well as IL-12 production was enhanced. BMDCs matured in the absence of E2 were unresponsive to TLR4 and TLR9 agonists, suggesting that the presence of E2 may be required for MyD88-dependent DC activation in response to microbial signals.
Thus, the study of Siracusa et al. may indicate that the up-regulated production of IFN-γ by CD11c(+) cells in response to 17β-estradiol stimulation may boost innate and adaptive immune responses. Previous studies illustrate that CD11c+NK1.1+ cells are a significant source of innate IFN-γ and innate production of IFN-γ by these cells is necessary for protection against Listeria monocytogenes.
Thus the study may provide an important mechanism regulating differences in the prevalence of autoimmune diseases and susceptibility to infection between sexes. The observation that E2 enhances production of IFN-γ by CD11c+ cells provides a key mechanism regulating the downstream differences in adaptive immunity, development of autoimmune disease, and susceptibility to microbial pathogens between the sexes.
Cover Image (right panel): Sex-biased regulation of T-cell response through E2-induced IFN type I (IFN-I) production. The E2–ERα axis controls the functional responses of diverse DC subsets along with IFN-I production. In females, upon 17β-estradiol (E2) stimulation plasmacytoid DC (pDCs) express enhanced interferon regulatory factor 5 (IRF-5) and reduced indoleamine 2,3-dioxygenase (IDO) leading to transient production of high levels of IFN-α that, in turn, stimulate CD8+ T-cell activity and downregulate regulatory T (Treg) cells. CD8+ T cell can also be stimulated by activation of BDCA3+ DCs, whose activation is interferon regulatory factor 8 (IRF-8) dependent. Moreover, the activity of CD8+ cells is directly modulated by the E2–ERα axis in a hormone dosage-dependent manner. In this context, IFN-I maybe the signal which, in some conditions such as the onset of the antitumor response restored by immune checkpoint inhibitor, drives a more powerful inflammatory cell-mediated immune response in female. From: Sexual Dimorphism of Immune Responses: A New Perspective in Cancer Immunotherapy, Front Immunol. 2018; 9: 552.; Published online 2018 Mar 21. doi: 10.3389/fimmu.2018.00552. Public domain.