The basis for personalized medicine is that unique aspects of our biology will define novel targets and strategies for more effective prevention and treatment of immune-related diseases. To develop such therapies, it is important to understand how our physiological parameters influence the immune responses. Despite the crucial role of the hormonal regulation on numerous biological processes, consideration for their influence on the immune system only start to emerge.
Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33–driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33–mediated lung in ammation. ILC2ps express the androgen receptor (Ar), and Ar signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic Ar expression limits IL-33–driven lung in ammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.