A Major Population of Functional KLRG1– ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers

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, consistent with recent reports that female lungs harbor greater numbers of GATA-3–dependent group 2 innate lymphoid cells (ILC2s). In this study, we determined whether sex hormone levels govern sex differences in the numbers, phenotype, and function of ILC2s in the murine lung 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 α (Esr1) deficiency showed that androgens rather than estrogens regulated numbers of the KLRG1− ILC2 subset and ILC2 functional capacity in the lung and BM, as well as levels of GATA-3 expression in BM ILC2s. Furthermore, the frequency of BM PLZF+ ILC precursors was higher in males and increased by excess androgens, suggesting that androgens act to inhibit the transition of ILC precursors 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.

The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms

“…ILC2 progenitor cells (ILC2Ps) in the bone morrow express androgen receptor (AR) mRNA although estrogen receptor ( Esr1 and Esr2 ) mRNA are undetectable . In male mice, the number of ILC2 progenitor cells is decreased, whereas the frequency of PLZF + ILC progenitor cells is increased, which suggests that endogenous androgen inhibits the differentiation of ILC2s. Furthermore, CD25 expression is decreased in male ILC2Ps and mature ILC2s.…”

Emerging therapeutic potential of group 2 innate lymphoid cells in acute kidney injury

“…There is also a growing body of evidence suggesting ILC2s exhibit sexual dimorphism. Depending on the tissue, ILC2s express androgen and estrogen receptors and this signaling can alter their activity [67][68][69][70][71] (Figure 1). Androgens suppress lung ILC2s and appear to inhibit differentiation of ILC2 progenitors from the bone marrow, whereas estrogen has the opposite effect on uterine ILC2s [67][68][69][70][71].…”

“…Depending on the tissue, ILC2s express androgen and estrogen receptors and this signaling can alter their activity [67][68][69][70][71] (Figure 1). Androgens suppress lung ILC2s and appear to inhibit differentiation of ILC2 progenitors from the bone marrow, whereas estrogen has the opposite effect on uterine ILC2s [67][68][69][70][71]. Interestingly, multiple reports have found that male mice have fewer tissue resident ILC2s within multiple organs, though it is not yet known whether this is the case in humans [67,69,71].…”

“…Androgens suppress lung ILC2s and appear to inhibit differentiation of ILC2 progenitors from the bone marrow, whereas estrogen has the opposite effect on uterine ILC2s [67][68][69][70][71]. Interestingly, multiple reports have found that male mice have fewer tissue resident ILC2s within multiple organs, though it is not yet known whether this is the case in humans [67,69,71]. Male mice are also more susceptible to kidney injury [21,72].…”

Identification of Group 2 Innate Lymphoid Cells in Mouse Lung, Liver, Small Intestine, Bone Marrow, and Mediastinal and Mesenteric Lymph Nodes

“…Female ILC2s are more responsive upon ex vivo cytokine stimulation compared to male, due to inhibitory effects of androgen signaling (Cephus et al., ; Laffont et al., ; Warren et al., ). It is also known that the number of ILC2s that are negative for KLRG1 in females increases with age and contributes to the higher numbers of ILC2s in female lungs (Kadel et al., ). This should be taken into consideration as well as the tissue‐dependent effect of sex hormones (Bartemes et al., ).…”