UC San Diego

Activation of the NLRP3-dependent inflammasome pathway is known to drive the progression of various autoimmune diseases. Interestingly, our recent studies on tissue-specific regulatory T cells (Tregs) indicate that elevated NLRP3 expression in intestinal Tregs is essential for their ability to suppress Th17 responses. Nevertheless, the precise effector mechanisms by which NLRP3 empowers gut Tregs to control Th17 cells remain unclear. Here we show that expression of IL-1β, a well-recognized proinflammatory cytokine and the primary product of NLRP3 inflammasome activation, by intestinal Treg cells is required for their regulation of Th17 responses. Increased Th17 responses in mice with Treg-specific IL-1β ablation led to aggravated inflammation specifically in the intestinal tissue. Mechanistically, our data suggests that Treg-derived IL-1β acts in an autocrine manner to drive high-level expression of IL-1Ra, an antagonist that can subsequently inhibit IL-1β signaling in other effector immune cell subsets. Collectively, this study redefines IL-1β, a downstream signaling molecule of NLRP3 traditionally associated with pro-inflammatory function, as a novel mediator of Treg suppression mechanism in the gut. Our findings also provide a gateway for future insights into Treg-mediated regulation of intestinal homeostasis.