STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection [IMMUNE REGULATION]

The appropriate orchestration of different arms of the immune response is critical during viral infection to promote efficient viral clearance while limiting immunopathology. However, the signals and mechanisms that guide this coordination are not fully understood. IFNs are produced at high levels during viral infection and have convergent signaling through STAT1. We hypothesized that STAT1 signaling during viral infection regulates the balance of innate lymphoid cells (ILC), a diverse class of lymphocytes that are poised to respond to environmental insults including viral infections with the potential for both antiviral or immunopathologic functions. During infection with respiratory syncytial virus (RSV), STAT1-deficient mice had reduced numbers of antiviral IFN-+ ILC1 and increased numbers of immunopathologic IL-5+ and IL-13+ ILC2 and IL-17A+ ILC3 compared with RSV-infected wild-type mice. Using bone marrow chimeric mice, we found that both ILC-intrinsic and ILC-extrinsic factors were responsible for this ILC dysregulation during viral infection in STAT1-deficient mice. Regarding ILC-extrinsic mechanisms, we found that STAT1-deficient mice had significantly increased expression of IL-33 and IL-23, cytokines that promote ILC2 and ILC3, respectively, compared with wild-type mice during RSV infection. Moreover, disruption of IL-33 or IL-23 signaling attenuated cytokine-producing ILC2 and ILC3 responses in STAT1-deficient mice during RSV infection. Collectively, these data demonstrate that STAT1 is a key orchestrator of cytokine-producing ILC responses during viral infection via ILC-extrinsic regulation of IL-33 and IL-23.


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