Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway

The cytokine IL-1 beta plays a central role in inflammatory responses that are initiated by microbial challenges, as well as in those that are due to endogenous processes (often called sterile inflammation). IL-1 beta secretion that occurs independently of microbial stimulation is typically associated with the presence of endogenous alarmins, such as extracellular ATP (an indicator of cytopathic damage). In this study, we show that IL-2-activated human invariant NKT (iNKT) cells stimulate the secretion of IL-1 beta protein by human peripheral blood monocytes in a manner that requires neither the presence of microbial compounds nor signaling through the extracellular ATP receptor P2X(7). Monocyte IL-1 beta production was specifically induced by iNKT cells, because similarly activated polyclonal autologous T cells did not have this effect. Secretion of IL-1 beta protein occurred rapidly (within 3-4 h) and required cell contact between the iNKT cells and monocytes. Similar to IL-1 beta production induced by TLR stimulation, the iNKT-induced pathway appeared to entail a two-step process involving NF-kappa B signaling and IL1 beta gene transcription, as well as assembly of the NLRP3 inflammasome and activation of caspase-1. However, in contrast to the classical inflammasome-mediated pathway of IL-1 beta production, activation of monocytes via P2X(7) was dispensable for iNKT-induced IL-1 beta secretion, and potassium efflux was not required. Moreover, the iNKT-induced effect involved caspase-8 activity, yet it induced little monocyte death. These results suggest that IL-2-activated human iNKT cells induce monocytes to produce IL-1 beta through a distinctive pathway that does not require the presence of microbial danger signals or alarmins associated with cytopathic damage.