NLRP3 gain-of-function in CD4+ T lymphocytes ameliorates experimental autoimmune encephalomyelitis.

NLRP3 inflammasome (NLR Pyrin-domain-containing 3) functions as an innate sensor of several PAMPs and DAMPs (pathogen- and damage-associated molecular patterns). It has been also reported as a transcription factor related to Th2 pattern, although its role in the adaptive immunity has been controversial, mainly because the studies were performed using gene deletion approaches. In the present study we have investigated the NLRP3 gain-of-function in the context of encephalomyelitis autoimmune disease (EAE), considered to be a Th1- and Th17-mediated disease. We took advantage of an animal model with NLRP3 gain-of-function exclusively to T CD4lymphocytes (CD4NLRP3). These mice presented reduced clinical score, accompanied by less infiltrating T CD4cells expressing both IFN-gand IL-17 at the central nervous system (CNS) during the peak of the disease. However, besides NLRP3 gain-of-function in lymphocytes, these mice lack NLRP3 expression in non-T CD4cells. Therefore, in order to circumvent this deficiency, we transferred naïve CD4Tcells from WT, NLRP3or CD4NLRP3into Rag-1mice and immunized them with MOG Likewise, the animals repopulated with CD4NLRP3TCD4cells presented reduced clinical score and decreased IFNgproduction at the peak of the disease. Additionally, primary effector CD4Tcells derived from these mice presented reduced glycolytic profile, a metabolic profile compatible with Th2 cells. Finally, naïveCD4Tcells from CD4NLRP3mice under a Th2-related cytokine milieu cocktail exhibited an increased IL-4 and IL-13 production. Conversely, naïveCD4Tcells from CD4NLRP3mice under Th1 differentiation produced less IFNgand T-bet. Altogether, our data evidences that the NLRP3 gain-of-function promotes a Th2-related response, a pathway that could be better explored in the treatment of multiple sclerosis.