Journal
CELLS
Volume 7, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/cells7090119
Keywords
Nlrp12; CNS; inflammation; T cell; EAE; spontaneous EAE; TCR signaling; 2D2
Categories
Funding
- MS Society of Canada
- Fonds de Recherche du Quebec-Sante (FRQS)
- Association de la sclerose en plaques de l'Estrie (ASPE)
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Although the etiology of multiple sclerosis (MS) remains enigmatic, the role of T cells is unquestionably central in this pathology. Immune cells respond to pathogens and danger signals via pattern-recognition receptors (PRR). Several reports implicate Nlrp12, an intracellular PRR, in the development of a mouse MS-like disease, called Experimental Autoimmune Encephalomyelitis (EAE). In this study, we used induced and spontaneous models of EAE, as well as in vitro T cell assays, to test the hypothesis that Nlrp12 inhibits Th1 response and prevents T-cell mediated autoimmunity. We found that Nlrp12 plays a protective role in induced EAE by reducing IFN gamma/IL-4 ratio in lymph nodes, whereas it potentiates the development of spontaneous EAE (spEAE) in 2D2 T cell receptor (TCR) transgenic mice. Looking into the mechanism of Nlrp12 activity in T cell response, we found that it inhibits T cell proliferation and suppresses Th1 response by reducing IFN and IL-2 production. Following TCR activation, Nlrp12 inhibits Akt and NF-B phosphorylation, while it has no effect on S6 phosphorylation in the mTOR pathway. In conclusion, we propose a model that can explain the dual immunoregulatory function of Nlrp12 in EAE. We also propose a model explaining the molecular mechanism of Nlrp12-dependent regulation of T cell response.
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