A Two-Cell Model for IL-1β Release Mediated by Death-Receptor Signaling

Abstract

Interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine that orchestrates the mobilization and activation of the immune system in response to infection. Its release is typically regulated by inflammasomes, multiprotein signaling platforms that assemble following the detection of pathogenic microorganisms and danger signals in the cytosol of host cells. However, many pathogens have evolved strategies to thwart inflammasome activation, yet there is a limited understanding of the countermeasures the immune system may employ to rescue IL-1β secretion during infection with inflammasome-evasive microbes. Invariant natural killer T (iNKT) cells are innate-like T cells that play a major role in host defense against bacterial, fungal, and viral infections. They exist in a poised effector state that endows them with the ability to rapidly transactivate other leukocytes through a wide range of mechanisms. Given their role as cellular adjuvants during the early stages of infection, we hypothesized that iNKT cells might contribute to the production of IL-1β by antigen-presenting cells (APCs), and that this may be important in the recognition of pathogens that evade inflammasome activation from within the cytosol of host cells. Here, we describe an alternative, two-cell model for IL-1β release where iNKT cells use the death-receptor pathway to instruct APCs to secrete IL-1β. Following cognate interactions with TLR-primed APCs, iNKT cells rapidly translocate pre-existing intracellular Fas ligand to the surface to engage Fas on APCs. Fas ligation activates a caspase-8-dependent signaling cascade in APCs that drives IL-1β release largely independent of the inflammasomes. Although Fas engagement initiates the apoptotic program in APCs, cells rapidly transition into a pyroptosis-like form of cell death mediated by the pore-forming protein gasdermin D. Importantly, we show that iNKT cells can employ FasL to elicit IL-1β release by APCs infected with the commensal microbe Bacteroides fragilis and the obligate intracellular pathogen Chlamydia trachomatis under conditions where these organisms fail to activate inflammasomes in a cell-intrinsic manner. Our findings demonstrate that iNKT cells are poised to deliver IL-1β-secretion signals through FasL, and this two-cell mechanism for IL-1β release may be important against microbes that fail to activate the inflammasomes from within the host cell cytosol.