STAT4 Directs a Protective Innate Lymphoid Cell Response to Gastrointestinal Infection

Abstract

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.

Receptor-targeted engineered probiotics mitigate lethal Listeria infection

“…Early production of interferon-gamma (IFNγ) is a critical step for generating an immune response and controlling Lm infection 50 . In the intestine, IFNγ is also involved in tissue homeostasis 51 and the transcription factor STAT4 promotes Lm- induced IFNγ production 52 . Therefore, we assessed the levels of IFNγ in BLP-treated mice.…”

Acute neonatal Listeria monocytogenes infection causes long-term, organ-specific changes in immune cell subset composition

“…Recent studies suggest that ILCs are essentially required to control early replication of Lm in the intestine and restrict dissemination of bacteria to peripheral tissues after oral infection in adult mice. In particular, ILC1 and ILC3 subsets respond to infection with proliferation and production of IFN-γ and IL-22, respectively [ 32 , 33 ]. Here, we asked whether neonatal Lm infections can long-lastingly affect the ILC compartment within the colon and mLNs.…”

“…In the present study, we established an acute neonatal Lm murine infection model with 1-day-old newborns by direct injection of Lm into the stomach to mimic the natural food-derived infection route, which results in a systemic dissemination of Lm to the mLNs, spleen and liver. Subsequently, we dissected the long-lasting consequences of neonatal Lm infection on major cell types of the immune system that were reported to be involved during Lm infection, namely T cells, ILCs and DCs [ 25–29 , 32 , 33 , 35 ]. In line with the previously reported organ-specific CD4+ and CD8 + T cell responses upon Lm infection [ 36 , 37 ], we observed long-term and organ-specific alterations in the CD4 + and CD8 + T cell compartment upon neonatal Lm infection.…”

Sustained post-developmental T-bet expression is critical for the maintenance of type one innate lymphoid cells in vivo

“…Overall, depletion of ILC1 had a beneficial effect in terms of colitis severity, but the caveat of this approach was a limited recovery of ILC1 cellularity, at least in the short-term. STAT1 and STAT4 signalling played no significant role in ILC1 maintenance and functionality ruling out a non-redundant role of signalling events elicited by IFNγ, IL-12 or IL-27 for instance (Dulson et al, 2019, Lighvani et al, 2001, Krause et al, 2006, Hibbert et al, 2003, Kamiya et al, 2004, Zhu et al, 2012. However, induced depletion of T-bet revealed a reduced expression of CD122 (IL-15RB), NKp46 and NK1.1 in cLP ILC1 a week prior to their loss in vivo.…”