Suppression of Inflammasome Activation by IRF8 and IRF4 in cDCs Is Critical for T Cell Priming
Margaret M. McDaniel,
Leah C. Kottyan,
Harinder Singh,
Chandrashekhar Pasare
Affiliations
Margaret M. McDaniel
Immunology Graduate Program, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Leah C. Kottyan
Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, USA
Harinder Singh
Center for Systems Immunology, Departments of Immunology and Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
Chandrashekhar Pasare
Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, USA; Corresponding author
Summary: Inflammasome activation leads to pyroptotic cell death, thereby eliminating the replicative niche of virulent pathogens. Although inflammasome-associated cytokines IL-1β and IL-18 have an established role in T cell function, whether inflammasome activation in dendritic cells (DCs) is critical for T cell priming is not clear. Here, we find that conventional DCs (cDCs) suppress inflammasome activation to prevent pyroptotic cell death, thus preserving their ability to prime both CD4 and CD8 T cells. Transcription factors IRF8 and IRF4, in cDC1s and cDC2s, respectively, mediate suppression of inflammasome activation by limiting the expression of inflammasome-associated genes. Overexpression of IRF4 or IRF8 inhibits inflammasome activation in macrophages, while reduced expression of IRF8 leads to aberrant inflammasome activation in cDC1s and hampers their ability to prime CD8 T cells. Thus, activation of inflammasome in DCs is detrimental to adaptive immunity, and our results reveal that cDCs use IRF4 and IRF8 to suppress this response.
