title: The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells.
abstract: 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(+)CD45RB(hi)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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Lukens
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Maggie J
authors.initials: MJ
authors.lastname: Barr
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Md Hasan
authors.initials: MH
authors.lastname: Zaki
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Brown
authors.affiliation: Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D007111:Immunity, Cellular; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C553199:NLRP12 protein, mouse; D015847:Interleukin-4