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

John R Lukens; Prajwal Gurung; Patrick J Shaw; Maggie J Barr; Md Hasan Zaki; Scott A Brown; Peter Vogel; Hongbo Chi; Thirumala-Devi Kanneganti

doi:10.1016/j.immuni.2015.03.006

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

Journal article

Open access

Peer reviewed

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

John R Lukens, Prajwal Gurung, Patrick J Shaw, Maggie J Barr, Md Hasan Zaki, Scott A Brown, Peter Vogel, Hongbo Chi and Thirumala-Devi Kanneganti

Immunity (Cambridge, Mass.), Vol.42(4), pp.654-664

04/21/2015

DOI: 10.1016/j.immuni.2015.03.006

PMCID: PMC4412374

PMID: 25888258

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https://doi.org/10.1016/j.immuni.2015.03.006View

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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.

Autoimmunity

Signal Transduction

Dermatitis, Atopic - genetics

CD8-Positive T-Lymphocytes - pathology

Colitis - genetics

Dendritic Cells - immunology

NF-kappa B - immunology

Dendritic Cells - pathology

Encephalomyelitis, Autoimmune, Experimental - immunology

Colitis - pathology

Intracellular Signaling Peptides and Proteins - immunology

CD4-Positive T-Lymphocytes - pathology

CD4-Positive T-Lymphocytes - immunology

Dermatitis, Atopic - immunology

Encephalomyelitis, Autoimmune, Experimental - genetics

Interleukin-4 - genetics

Ataxia - genetics

Colitis - immunology

Intracellular Signaling Peptides and Proteins - genetics

Macrophages - immunology

Ataxia - pathology

Ataxia - immunology

Encephalomyelitis, Autoimmune, Experimental - pathology

Macrophages - pathology

Gene Expression Regulation

Dermatitis, Atopic - pathology

Mice, Knockout

Interleukin-4 - immunology

Animals

NF-kappa B - genetics

Mice

CD8-Positive T-Lymphocytes - immunology

Immunity, Cellular

Details

Title: Subtitle: The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells
Creators: John R Lukens - 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
Prajwal Gurung - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Patrick J Shaw - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Maggie J Barr - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Md Hasan Zaki - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Scott A Brown - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Peter Vogel - Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Hongbo Chi - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Thirumala-Devi Kanneganti - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org
Resource Type: Journal article
Publication Details: Immunity (Cambridge, Mass.), Vol.42(4), pp.654-664
DOI: 10.1016/j.immuni.2015.03.006
PMID: 25888258
PMCID: PMC4412374
ISSN: 1074-7613
eISSN: 1097-4180
Grant note: R01 AI101935 / NIAID NIH HHS 281600 / European Research Council R01 CA163507 / NCI NIH HHS P30 CA021765 / NCI NIH HHS R01 AR056296 / NIAMS NIH HHS AI101935 / NIAID NIH HHS CA163507 / NCI NIH HHS AR056296 / NIAMS NIH HHS
Language: English
Date published: 04/21/2015
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094390702771

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