Innate lymphoid cells (ILCs) are strategically positioned at mucosal barrier surfaces where they respond quickly to infection or injury. Therefore, we hypothesized that ILCs are key contributors to the early immune response in the intestine against Listeria monocytogenes. Using a modified strain of L. monocytogenes that mimics human gastrointestinal listeriosis in mice, we find ILCs to be essential for control of early replication of L. monocytogenes in the intestine as well as for restricted dissemination of bacteria to peripheral tissues. Specifically, group 1 ILCs (ILC1s) and group 3 ILCs (ILC3s) respond to infection with proliferation and IFN-γ and IL-22 production. Mechanistically, we show that the transcription factor STAT4 is required for the proliferative and IFN-γ effector response by ILC1s and ILC3s, and loss of STAT4 signaling in the innate immune compartment results in an inability to control bacterial growth and dissemination. Interestingly, STAT4 acts acutely as a transcription factor to promote IFN-γ production. Together, these data illustrate a critical role for ILCs in the early responses to gastrointestinal infection with L. monocytogenes and identify STAT4 as a central modulator of ILC-mediated protection.
Group 3 innate lymphoid cells (ILC3s) have dual roles in intestinal health, acting in both protective and pathogenic capacities, and importantly, modulations in this population of ILCs have been implicated in inflammatory bowel disease (IBD). Further, subpopulations of ILC3s have been described as serving specific functions in maintaining homeostasis or responding to infection, and aberrant activation of one or more of these subpopulations could exacerbate IBD. However, the signals that enforce the protective and pathogenic features of ILC3s are not fully elucidated. Here we show that IL-21, a cytokine primarily produced by CD4 T cells, acts on a subpopulation of intestinal ILC3s to promote a protective phenotype. IL-21 signaling does not affect the MHCII expressing ILC3 subset but promotes ILC3s that express Tbet and are poised to produce IL-22. Consistent with a protective phenotype, IL-21-deficiency dampens cytokine-induced IL-17A production. We show that exacerbated colitis develops in mice lacking the IL-21 receptor, in agreement with a protective role for IL-21 signaling on ILC3s. These data reveal a novel role for IL-21 in shaping ILC responses in the intestine and provide one mechanism by which effector CD4 T cells can influence innate immunity.
Zika virus (ZIKV) is transmitted by mosquitoes, similar to other flaviviruses. However, ZIKV is unusual among flaviviruses in its ability also to spread through sexual transmission.
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