UC San Diego

Regulatory T (Treg) cells are a subset of adaptive immune cells known for their immunosuppressive functions. Emerging evidence demonstrates that Treg exist throughout the body in tissue-specific sub-populations with specialized functions. RNA-seq analysis performed on mice during systemic autoimmune inflammation revealed high expression levels of Nod-like receptor protein 3 (NLRP3) in gut-resident Treg cells. NLRP3 is part of well-characterized inflammasome commonly associated with innate immune cells, but is beginning to be appreciated in adaptive immune cells as well. To determine the role of NLRP3 in gut-resident Treg-mediated immunosuppression, we generated bone marrow chimeras (BMC) and found that NLRP3-deficiency in Treg cells does not contribute to Treg development or homeostasis, but does result in increased Teff production of IL-17A in the colon. Moreover, in an adoptive T cell transfer model of colitis, co-transfer of NLRP3KO Treg cells failed to rescue Rag-/- recipient mice from weight loss and led to increased Teff production of IFN- and IL-17A in the colon. Moreover, to gain further insights into the role of NLRP3 in Treg cells, in addition to the aforementioned studies with NLRP3KO Treg cells, we also generated a mouse model in which NLRP3 is constitutively-activated in a Treg-specific manner (Foxp3creNLRP3iCA). After immunologically challenging these mice via Citrobacter rodentium, we have shown that colonic Foxp3creNLRP3iCATreg cells exhibit enhanced control over Teff production of IFN- which could potentially impact bacterial clearance. Collectively, by taking both loss-of-function and gain-of-function approaches, our data reveals a pivotal role of NLRP3 in gut-associated Treg cells in maintaining intestinal homeostasis.