Androgens protect ILC2S from functional suppression during influenza virus infection

Biological sex differences in morbidity upon influenza A virus (IAV) infection are linked to stronger IFN-centered immune responses in females, yet the regulatory role of sex steroid receptors in immune cell subsets is incompletely understood. Lung-resident group 2 innate lymphoid cells (ILC2s) express notably high levels of androgen receptors (AR). In IAV infection, ILC2s produce type 2 cytokines and facilitate tissue repair, but they also may be functionally suppressed by type 1 cytokines. Here, we report sex differences in the magnitude of ILC2 functional suppression at the peak of sublethal IAV infection. Relative to males, ILC2s in females show attenuated proliferation, decreased propensity for IL-5 and amphiregulin production, and reduced expression of GATA3 and IL-33R, features supported by divergent transcriptomes. Equivalent inflammatory cytokine levels and viral load suggested sex differences in ILC2-intrinsic factors. Indeed, naïve female ILC2s showed elevated IFNGR expression and higher phospho-STAT1 levels following IFNγ stimulation, and lymphocyte-restricted STAT1 deficiency reversed IAV-induced suppression of female ILC2s. ILC2-restricted AR deficiency increased IFNGR expression and loss of androgens via orchiectomy led to suppression of male ILC2s. Thus, ILC2-intrinsic AR activity attenuates IFNGR-STAT1 signaling pathways to preserve canonical ILC2 function in males during IAV infection.