Suppression of Inflammasome Activation by IRF8 and IRF4 in cDCs is Critical for T cell Priming

Abstract

Abstract 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 discover that inflammasome activation in conventional DCs (cDCs) is detrimental to the induction of adaptive immunity. We found that lymphoid organ resident cDCs actively suppress inflammasome activation to avoid pyroptotic cell death. This protection from inflammasome-induced cell death is critical for both CD4 and CD8 T cell priming. Transcription factors IRF8 and IRF4, in cDC1s and cDC2s respectively, mediate this suppression of inflammasome activation by limiting the expression of inflammasome-associated genes. We show that reduced expression of IRF8 leads to aberrant inflammasome activation in cDC1s which hampers subsequent CD8 T cell priming. Conversely, overexpression of either of IRF4 or IRF8 is sufficient to inhibit inflammasome activation in macrophages. These results uncover the molecular mechanism of inflammasome suppression in cDCs, and ascribe a novel post-developmental role for IRF4 and IRF8 in cDC function.