| iNKT cells are known to be highly pro-inflammatory, and by understanding the cellular interactions that drive iNKT cell-induced sterile inflammation, we may be able to develop novel therapeutics that will enable us to curtail this response when it contributes to disease. Human clonal iNKT cells were co-cultured with freshly isolated human monocytes to examine the functional consequences of iNKT cell-monocyte interactions. We found that monocytes co-cultured with iNKT cells are rapidly induced to secrete a variety of pro-inflammatory mediators, including IL-1beta. This effect was specific to iNKT cells---neither freshly isolated nor cultured conventional T cells induced monocytes to secrete IL-1beta. Induction of monocytic IL-1beta production and secretion by iNKT cells was found to occur through the alternative pathway of NLRP3 inflammasome activation. iNKT cell-induced IL-1beta is dependent on both caspase-8 and caspase-1 activation, but receipt of a second signal capable of inducing potassium efflux was dispensable. Unlike the classical pathway of NLRP3 activation, secretion of IL-1beta was associated with little cell death. We also examined the capacity of iNKT cells to induce the secretion of prostaglandins by antigen-presenting cells. The interaction of iNKT cells with dendritic cells leads to the generation of prostaglandins such as PGE 2 via ATP secretion; secretion of ATP drives calcium influx and the activation of PLA2. Interestingly, though monocytes do not appear to flux calcium in response to iNKT cell contact, the interaction of monocytes and iNKT cells also results in the generation of PGE2. Like IL-1beta production, this effect was also specific to iNKT cells and was dependent on direct cell contact. Currently, the pathway underlying iNKT cell induction of PGE2 secretion by monocytes remains an open question, though the generation of reactive oxygen species may be key. Future experiments, using primary human cells and pathological specimens, may further reveal how iNKT cell-monocyte interactions contribute directly to pathology. Developing strategies to specifically target the consequences of iNKT cell-induced inflammation may be more effective at preventing pathology than targeting iNKT cells globally. As such, a clear understanding of the mechanisms and consequences of iNKT cell-antigen-presenting cell interactions is essential in order to design effective therapies. |
