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STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells
during Viral Infection
#MMPMID28576981
Stier MT
; Goleniewska K
; Cephus JY
; Newcomb DC
; Sherrill TP
; Boyd KL
; Bloodworth MH
; Moore ML
; Chen K
; Kolls JK
; Peebles RS Jr
J Immunol
2017[Jul]; 199
(2
): 510-519
PMID28576981
show ga
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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