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bioRxiv · 10.1101/2025.01.23.634583

ANDROGENS PROTECT ILC2S FROM FUNCTIONAL SUPPRESSION DURING INFLUENZA VIRUS INFECTION

Kadel, S.·Miller, R. A. J.·Karlik, A.·Turner, S.·Williams, A. P.·Ainsua-Enrich, E.·Hatipoglu, I.·Bagavant, H.·Alberola-Ila, J.·Garton, J.·Pelikan, R.·Kovats, S.
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Abstract

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 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 cytokines. 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 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, naive female ILC2s showed elevated IFNGR expression and higher phospho-STAT1 levels following IFN{gamma} 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. These data support the hypothesis that intrinsic AR activity regulates IFNGR-STAT1 signaling pathways to preserve canonical ILC2 function in males during IAV infection.

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Kadel, S., Miller, R. A. J., Karlik, A., Turner, S., Williams, A. P., Ainsua-Enrich, E., Hatipoglu, I., Bagavant, H., Alberola-Ila, J., Garton, J., Pelikan, R., Kovats, S.. 2025-01-25. ANDROGENS PROTECT ILC2S FROM FUNCTIONAL SUPPRESSION DURING INFLUENZA VIRUS INFECTION. https://doi.org/10.1101/2025.01.23.634583

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