Androgen Receptor Activity Underlies Sex Differences In Lung-Resident Ilc2 Functional Responses During Influenza Virus Infection

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. ILC2s in naive male mice with lymphocyte-restricted AR deficiency displayed levels of IFNGR comparable to female mice, suggesting AR activity underlies sex differences in intrinsic IFNGR expression. Early life orchiectomy revealed that endogenous androgens decreased ILC2 numbers but protected males from suppression of ILC2s in IAV infection. Taken together, our data show that AR activity preserves canonical ILC2 function in males during IAV infection and may help to explain the documented human gender differences in immunity to IAV.