NLRP3 confers regulatory T cell-mediated control of intestinal inflammation 2256029

Abstract

Inflammasome activation is an essential component of innate immunity. Recently, its role in regulating various T cell responses has also become increasingly recognized. Interestingly, we found increased expression of Nlrp3 and many genes associated with the NLRP3 inflammasome pathway in intestinal regulatory T cells (Tregs) from mice with autoimmune-mediated inflammation. This unexpected finding of a pro-inflammatory pathway upregulated in a cell type typically known for suppressing immune responses called for further investigation. We developed a new mouse model with a Treg-specific deletion of Nlrp3 and subjected the mice to a variety of disease models of intestinal inflammation. We then performed RNA-seq on NLRP3-sufficient and NLRP3-deficient intestinal Tregs isolated from a similar inflammatory environment to gain mechanistic insights. To further characterize the subset of intestinal Tregs that upregulated Nlrp3, we used the novel PrimeFlow RNA Assay. In multiple disease models, loss of NLRP3 in Tregs led to elevated Th17 responses accompanied by reduced Th1 responses despite similar Treg frequencies and comparable levels of Foxp3 expression. Mechanistically, NLRP3 likely confers Treg suppressor function against Th17 cells through driving the production of molecules that antagonize IL-1 signaling. Collectively, we demonstrate a previously underappreciated anti-inflammatory role of NLRP3 in Tregs in controlling Th17 responses in the intestines. Ultimately, our work should guide effective therapies for intestinal disorders where the anti-inflammatory vs. proinflammatory role of NLRP3 is still debated. NIDDK F31 2023-2025 and Biolegend Fellow in Immunology 2021-2022 Immune Response Regulation: Cellular Mechanisms (IRC)