ANDROGENS PROTECT ILC2S FROM FUNCTIONAL SUPPRESSION DURING INFLUENZA VIRUS INFECTION.

Area of Science:

• Immunology
• Virology
• Endocrinology

Background:

• Biological sex influences influenza A virus (IAV) morbidity, partly via immune responses.
• Females exhibit stronger interferon-centered immunity, but sex hormone receptor roles in immune cells are unclear.
• Lung-resident group 2 innate lymphoid cells (ILC2s) express androgen receptors (AR) and are crucial for IAV infection repair but can be suppressed by type 1 cytokines.

Purpose of the Study:

• To investigate sex differences in lung ILC2 functional suppression during IAV infection.
• To elucidate the role of androgen receptors (AR) and interferon signaling in sex-based ILC2 regulation.

Main Methods:

• Comparative analysis of lung ILC2s from male and female mice during sublethal IAV infection.
• Assessment of ILC2 proliferation, cytokine production, GATA3 and IL-33R expression.
• Transcriptome analysis, IFNγ stimulation assays, and STAT1/AR deficiency models.

Main Results:

• Female ILC2s exhibited attenuated proliferation, reduced IL-5/amphiregulin production, and lower GATA3/IL-33R expression compared to males.
• Female ILC2s showed elevated IFNGR expression and higher phospho-STAT1 levels post-IFNγ stimulation.
• Lymphocyte-restricted STAT1 deficiency reversed IAV-induced suppression in female ILC2s, while AR deficiency or androgen loss suppressed male ILC2s.

Conclusions:

• Intrinsic factors in female ILC2s contribute to their functional suppression during IAV infection.
• Androgen receptor (AR) activity in males regulates IFNGR-STAT1 signaling, preserving ILC2 function.
• These findings highlight AR's role in modulating immune cell responses based on sex during viral infections.