Sex differences in ILC2 function in influenza result from imprinted donor sex intrinsic factors independent of host sex in competitive female-male bone marrow chimeras

Historical influenza pandemics and the SARS-CoV-2 pandemic revealed gender differences in morbidity of respiratory virus infections. In human or murine influenza A virus (IAV) infection, females of reproductive age generate stronger innate and adaptive antiviral responses leading to immunopathology, while elderly males often experience more severe disease. Sex hormone levels play a role in this disparity, yet little is known about cell intrinsic regulation of immune cells by estrogen or androgen receptors (AR). Lung resident type 2 innate lymphocytes (ILC2s) express high levels of AR, a nuclear hormone receptor that regulates chromatin via epigenetic modifications. While female lungs contain higher ILC2 numbers in homeostasis, we showed that ILC2s in females were preferentially functionally suppressed during IAV infection, whereas ILC2s in males retained robust type 2 function, including IL-5 production. Here, we determined if sex differences in pulmonary ILC2s result from extrinsic factors present in host environments or from imprinted donor-intrinsic factors. We set up competitive bone marrow chimeras by transferring a mix of female and male lineage-depleted bone marrow cells into either male or female hosts. Female hosts harbored more pulmonary ILC2s than male hosts, suggesting the extrinsic sex hormone environment regulates ILC2 numbers. Upon IAV infection, an increased fraction of ILC2s from male donors retained high IL33R expression and produced IL-5, regardless of host sex, suggesting donor sex-intrinsic factors regulate the canonical ILC2 functional response. We are now testing the hypothesis that androgens/AR activity epigenetically imprint genes regulating type 2 function in male ILC2s upon sexual maturity.