Caspase-1-Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

IL-1 beta plays a critical role in promoting IL-17 production by gamma delta and CD4 T cells. However, IL-1-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1 beta and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1-processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1 beta and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1 beta or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and gamma delta T cells in vivo and attenuated the clinical signs of EAE. gamma delta T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1 beta and IL-23, stimulated IL-17 production by gamma delta T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1 beta and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1 beta and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases. The Journal of Immunology, 2011, 186: 5738-5748.