Abstract
The innate immune response following infection with entero-invasive bacterial species is triggered upon release of cyclic di-guanylate monophosphate (c-di-GMP) into the host cell cytosol. Bacterial c-di-GMP activates the intracellular Sensor Stimulator of Interferon Genes (STING), encoded by Tmem173 in mice. Here we identify Interferon Regulatory Factor (IRF) 1 as a critical effector of STING-mediated microbial DNA sensing that is responsible for TH17 cell generation in the mucosal immune system. We find that STING activation induces IRF1-dependent transcriptional programs in dendritic cells (DCs) that define T cell fate determination, including induction of Gasdermin D, IL-1 family member cytokines, and enzymes for eicosanoid synthesis. Our results show that IRF1-dependent transcriptional programs in DCs are a prerequisite for antigen-specific TH17 subspecification in response to microbial c-di-GMP and Salmonella typhimurium infection. Our identification of a STING-IRF1 signaling axis for adaptive host defense control will aid further understanding of infectious disease mechanisms.
Highlights
The innate immune response following infection with entero-invasive bacterial species is triggered upon release of cyclic di-guanylate monophosphate (c-di-GMP) into the host cell cytosol
The induction of IL-17A by c-di-GMP required Stimulator of Interferon Genes (STING) signaling as intranasal immunizations in Tmem173−/−;Il17a-GFP reporter mice resulted in significantly less IL-17A-expressing T cells in cervical lymph node (CLN) and mesenteric lymph nodes (MLNs) compared to wild-type mice (Fig. 1b)
To determine whether STING signaling was able to activate mucosal dendritic cells (DCs), we crossed Tmem173−/− mice into the CAG::KikGR (KikGR) background to be able to track the migration of lamina propria (LP)-DCs after photoconversion in response to c-di-GMP
Summary
The innate immune response following infection with entero-invasive bacterial species is triggered upon release of cyclic di-guanylate monophosphate (c-di-GMP) into the host cell cytosol. We identify Interferon Regulatory Factor (IRF) 1 as a critical effector of STING-mediated microbial DNA sensing that is responsible for TH17 cell generation in the mucosal immune system. Our results show that IRF1-dependent transcriptional programs in DCs are a prerequisite for antigen-specific TH17 subspecification in response to microbial c-diGMP and Salmonella typhimurium infection. IRF1 mediates cell type-specific transcriptional programs that are key to host defenses initiated by a wide range of microbial pattern recognition receptors, such as Toll-like receptor (TLR), RIG-I like receptors, and cytokine receptors[18]. We identified the STING–IRF1 signaling axis as essential for the control of mucosal TH17 cell responses that signify protective host defense activation against entero-invasive pathogen such as S. typhimurium
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