STAT4 is required for protective Innate Lymphoid Cell responses to gastrointestinal infection

Abstract

Abstract Innate Lymphoid Cells (ILCs) are a newly discovered subset of cells that serve both protective and pathogenic roles in intestinal health. ILCs consist of three defined subgroups and perform effector functions similar to CD4 T cells. However, ILCs lack a specific antigen receptor and are activated directly by cytokines early during an immune response. Since the initial events in an immune response can dictate the ability of the host to control intestinal infection, it is critical to identify molecules that regulate ILC function. Signal transducer and activator of transcription 4 (STAT4) is important for driving many pro-inflammatory responses and phenotypes in T cells, but its effects on ILC development and function remain unclear. Contrary to its known role in Th1 cell biology, we find STAT4 to be dispensable in Group 1 ILC (ILC1) development. However, we observe that STAT4 is critical for IFN-γ production by ILC1s, thus influencing the capacity of this subgroup to mount an effector response. Whereas STAT4 deficiency did not impact IL-22 or IL-17 production by ILC3s, the transcription factor specifically modulates IFNγ production by a plastic Tbet+ subgroup of ILC3s that is greatly expanded in response to inflammation. Importantly, STAT4 signaling is also critical for survival against a genetically modified strain of Listeria monocytogenes that is able to model human Listeriosis in mice. Furthermore, both ILC1 and ILC3 respond to infection with robust IFNγ production, and when ILCs are depleted mice are unable to mount a protective innate response and succumb earlier to infection. These results indicate that STAT4 signaling influences critical responses by ILCs, thereby contributing to host protection against intestinal infection.