Androgens regulate sex differences in lung-resident ILC2 functional responses during influenza virus infection

Autor: Sapana Kadel, Sean Turner, Anna Karlik, Reegan Miller, Erola Ainsua-Enrich, Susan Kovats
Rok vydání: 2021
Předmět:
Zdroj: The Journal of Immunology. 206:55.15-55.15
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.206.supp.55.15
Popis: Lung-resident group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines and facilitate tissue repair in response to alarmins such as IL-33 released during respiratory virus infection, but they also may be functionally suppressed by type 1 cytokines. Lung ILC2s express notably high levels of intracellular androgen receptor (AR) compared to ILC1s, T and B cells. To test the hypothesis that females and males show differential ILC2 responses in influenza virus (IAV) infection, we analyzed the numbers and functional responses of lung ILCs in IAV infected mice. On days 3–10 post-infection, lungs of female mice contained greater numbers of ILC2s and ILC1s compared to males. However, the female ILC2s were preferentially suppressed at the peak of infection, with a dampened type 2 program manifest as attenuated proliferation, decreased IL-5 and amphiregulin production, reduced expression of GATA-3 and IL-33R and increased surface IFNGR. IFNG levels in the lung were comparable between sexes at day 7 post-infection, suggesting intrinsic differences in ILC2 responses to interferons. Indeed, naïve female ILC2s showed higher expression of IFNGR and higher phospho-STAT1 levels following stimulation by IFNG. Early life orchiectomy revealed that endogenous androgens decreased ILC2 numbers but protected males from suppression of ILC2s in IAV infection. Furthermore, single cell RNA-sequencing experiments revealed that female ILC2s were enriched in a “suppressed ILC2” cluster while male ILC2s were enriched in a “proliferating ILC2” cluster on day 7 post-infection. Taken together, our data show that AR activity preserves canonical ILC2 function in males during IAV infection and may help to explain known gender differences in immunity to IAV.
Databáze: OpenAIRE
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