The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells

Missense mutations in the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing family of gene 12 (Nlrp12) are associated with periodic fever syndromes and atopic dermatitis in humans. Here, we have demonstrated a crucial role for NLRP12 in negatively regulating patho...

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Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Mass.), 2015-04, Vol.42 (4), p.654-664
Main Authors:	Lukens, John R., Gurung, Prajwal, Shaw, Patrick J., Barr, Maggie J., Zaki, Md. Hasan, Brown, Scott A., Vogel, Peter, Chi, Hongbo, Kanneganti, Thirumala-Devi
Format:	Article
Language:	eng
Subjects:	Animals Ataxia Ataxia - genetics Ataxia - immunology Ataxia - pathology Autoimmunity CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - pathology CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - pathology Colitis - genetics Colitis - immunology Colitis - pathology Cytokines Dendritic Cells - immunology Dendritic Cells - pathology Dermatitis, Atopic - genetics Dermatitis, Atopic - immunology Dermatitis, Atopic - pathology Disease Encephalomyelitis, Autoimmune, Experimental - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - pathology Gene Expression Regulation Histopathology Immune system Immunity, Cellular Inflammatory bowel disease Interleukin-4 - genetics Interleukin-4 - immunology Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - immunology Kinases Laboratories Lymphocytes Macrophages - immunology Macrophages - pathology Mice Mice, Knockout NF-kappa B - genetics NF-kappa B - immunology Paralysis Peptides Rodents Signal Transduction Studies T cell receptors
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Summary:	Missense mutations in the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing family of gene 12 (Nlrp12) are associated with periodic fever syndromes and atopic dermatitis in humans. Here, we have demonstrated a crucial role for NLRP12 in negatively regulating pathogenic T cell responses. Nlrp12−/− mice responded to antigen immunization with hyperinflammatory T cell responses. Furthermore, transfer of CD4+CD45RBhi Nlrp12−/− T cells into immunodeficient mice led to more severe colitis and atopic dermatitis. NLRP12 deficiency did not, however, cause exacerbated ascending paralysis during experimental autoimmune encephalomyelitis (EAE); instead, Nlrp12−/− mice developed atypical neuroinflammatory symptoms that were characterized by ataxia and loss of balance. Enhanced T-cell-mediated interleukin-4 (IL-4) production promotes the development of atypical EAE disease in Nlrp12−/− mice. These results define an unexpected role for NLRP12 as an intrinsic negative regulator of T-cell-mediated immunity and identify altered NF-κB regulation and IL-4 production as key mediators of NLRP12-associated disease. •Deficiency in NLRP12 promotes the generation of hyperinflammatory T cell responses•Induction of EAE in Nlrp12−/− mice results in atypical neuroinflammatory disease•NLRP12 is an intrinsic regulator of T cells•Dysregulated IL-4 production causes T-cell-induced inflammation in Nlrp12−/− mice Kanneganti et al. identify the NOD-like receptor protein, NLRP12, as a novel negative regulator of T cell activation. Their work defines a T-cell-autonomous role for NLRP12 in the suppression of inflammatory cytokine production and suggests that dysregulated NLRP12-mediated signaling in T cells is sufficient to drive inflammatory disease.
ISSN:	1074-7613 1097-4180