Abstract
Abstract Biological sex differences in morbidity upon influenza A virus (IAV) infection are linked to stronger interferon-centered immune responses in females, yet the regulatory role of sex hormone 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 inflammation. Here we report sex differences in the magnitude of lung ILC2 functional suppression at the peak of sublethal IAV infection. Relative to males, ILC2s in female lungs showed attenuated proliferation, decreased propensity for IL-5 and amphiregulin production and reduced expression of GATA3 and IL-33R. Single cell RNA sequencing revealed sex-divergent transcriptomes, with female cells preferentially present in clusters of stressed, functionally suppressed ILC2s and male cells dominating in clusters of canonically activated ILC2s. 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 IFNG stimulation, and lymphocyte-restricted STAT1 deficiency reversed IAV-induced suppression of female ILC2s. Lymphocyte-restricted AR deficiency or loss of androgens via orchiectomy led to increased IFNGR expression and suppression of male ILC2s. Collectively, these data show that ILC2-intrinsic AR activity regulates IFNGR-STAT1 signaling pathways to preserve canonical ILC2 function in males during IAV infection. Supported by grants from NIH (HL 119501) and the Presbyterian Health Foundation
Published Version
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