A functional androgen-regulated subset lacking KLRG1 contributes to the sex bias in ILC2s

Abstract

Abstract Humans show significant sex differences in the incidence and severity of respiratory diseases including asthma and virus infection. Sex hormones contribute to the female sex bias in type 2 inflammation associated with respiratory diseases, including greater numbers of group 2 innate lymphoid cells (ILC2s). We determined if sex hormone levels govern sex differences in the numbers, phenotype and function of ILC2s in the murine lungs and bone marrow (BM). Our data show that lungs of female mice harbor significantly greater ILC2 numbers in homeostasis, in part due to a major subset of ILC2s lacking killer-cell lectin like receptor G1 (KLRG1), a population largely absent in male lungs. The KLRG1− ILC2s were capable of type 2 cytokine production and increased with age after sexual maturity, suggesting that a unique functional subset exists in females. Experiments with gonadectomized mice or mice bearing either global or lymphocyte restricted estrogen receptor alpha deficiency showed that androgens rather than estrogens regulated these ILC2 phenotypes in the lungs. While BM ILC2 numbers were similar in both sexes, male levels of androgens led to a significant population of functional KLRG1+ ILC2s. However, mice with abnormally elevated androgens showed a reduced frequency of BM ILC2s with decreased expression of the transcription factor GATA-3 required for the development of ILC2s. Furthermore, the numbers of BM PLZF+ILC precursors (ILCPs) were higher in males and increased by excess androgens, suggesting that androgens act to inhibit the transition of ILCPs to ILC2s. Taken together, these data show that a functional subset of KLRG1− ILC2s in females contributes to the sex bias in lung ILC2s that is observed after reproductive age.