Dendritic Cells Suppress Pathogen-Induced Inflammasome Activation to Prime Naïve T Cells




McDaniel, Margaret Mae

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Activation of inflammasome leads to pyroptotic cell death thereby eliminating the replicative niche of virulent pathogens, a process integral to innate immunity. While inflammasome-associated cytokines such as 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 lymphoid organ resident conventional DCs (cDCs) actively suppress inflammasome activation to prevent pyroptotic cell death. This protection from inflammasome-induced cell death preserves the ability of cDCs to prime both CD4 and CD8 T cells. Transcription factors IRF8 and IRF4, in cDC1s and cDC2s respectively, mediate this suppression of inflammasome activation by limiting the expression of inflammasome-associated genes. Additionally, overexpression of either of IRF4 or IRF8 is sufficient to inhibit inflammasome activation in macrophages, cells that are normally permissive to inflammasome activation. Furthermore, we find that reduced expression of IRF8 leads to aberrant inflammasome activation in cDC1s which hampers their ability to prime CD8 T cells. These results uncover the importance as well as the molecular mechanism of inflammasome suppression in cDCs and ascribe a novel post-developmental role for IRF4 and IRF8 in cDC function.

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