Type-2 immune responses are characterized by secretion of IL4, IL5, IL9, and IL13. This specific “cytokine signature” is essential to control parasitic infections, but is also associated with allergic reactions; these responses involve the coordinated action of group-2 innate lymphoid cells (ILC2s) and Th2 lymphocytes. ILC2s are rapid-responders and potent producers of these type-2 cytokines. They are widely distributed at mucosal surfaces, where they can be activated by epithelial stress-signals –– such as thymic stromal lymphopoietin, IL25, and IL33. In response to these stimuli, ILC2s secrete large amounts of IL5, IL13, and IL9.
The secretion of IL5 by the ILC2s leads to recruitment and activation of eosinophils and mast cells, whereas IL13 activates goblet cells and mucous production by epithelial cells. In addition, IL13 production by ILC2s is an active determinant to mount an effective Th2 cell response by instructing dendritic cells (DCs) to prime Th2 cells in draining lymph nodes. Thus, ILC2s have recently emerged as critical cells in the initiation of allergic inflammatory responses such as asthma or atopic dermatitis. Besides cytokines, additional mediators –– including the arachidonic acid metabolites leukotriene D4 (LTD4) and prostaglandin D2 (PGD2) –– appear to be potent regulators of ILC2 function.
The immunologists’ current understanding of the homeostatic regulation of ILC2 is quite limited, however, and whether other endogenous factors –– such as sex steroid hormones –– also influence ILC2 responses is currently not clear. Asthma is a hallmark of type-2 immune response–mediated disease causing chronic inflammation of the airways. Both clinical studies and mouse models discovered that asthma incidence, prevalence, and severity differ according to sex. Although males are more susceptible to asthma than females in childhood, onset of puberty reverses that trend for most allergic disorders. The drop in asthma incidence observed, in and around the time of puberty in males, suggests a protective action of male sex hormones. Consistent with these observatins, hypogonadism has been associated with enhanced susceptibility to asthma, when compared with men having normal testosterone levels. Although these opinions support a protective role for androgens in susceptibility to allergic asthma, the underlying mechanisms responsible for this effect are unknown.
In the very recent publication [attached], authors show that ILC2 development is substantially influenced by male sex hormones. Male mice have decreased numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues, compared with that in females. Consequently, males exhibit diminished susceptibility to allergic airway inflammation in response to environmental allergens, and less severe IL33–driven lung inflammation –– which is correlated with an impaired expansion of lung ILC2s. Notably, removal of male gonads, but not female ovaries, abolishes the sex differences in ILC2 development and restores IL33–mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits differentiation of ILC2Ps into mature ILC2s. Authors also demonstrate that hematopoietic AR expression limits IL33–driven lung inflammation by way of a cell-intrinsic inhibition of ILC2 expansion. Therefore, authors conclude that male (but not female) sex hormones play a pivotal protective role in type-2 airway inflammation by negatively regulating ILC2 homeostasis –– thereby limiting the capacity of ILC2s to expand locally in response to IL33.
J Exp Med. http://doi.org/b6wn (2017)