Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis.
Dendritic cells (DCs), which are known to support immune activation during infection, may also regulate immune homeostasis in resting animals. Here we show that mice lacking the ubiquitin-editing molecule A20 specifically in DCs spontaneously showed DC activation and population expansion of activated T cells. Analysis of DC-specific epistasis in compound mice lacking both A20 and the signaling adaptor MyD88 specifically in DCs showed that A20 restricted both MyD88-independent signals, which drive activation of DCs and T cells, and MyD88-dependent signals, which drive population expansion of T cells. In addition, mice lacking A20 specifically in DCs spontaneously developed lymphocyte-dependent colitis, seronegative ankylosing arthritis and enthesitis, conditions stereotypical of human inflammatory bowel disease (IBD). Our findings indicate that DCs need A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.
Department of Medicine, University of California at San Francisco, San Francisco, California, USA.
Gianna Elena
GE
Hammer
Emre E
EE
Turer
Kimberly E
KE
Taylor
Celia J
CJ
Fang
Rommel
R
Advincula
Shigeru
S
Oshima
Julio
J
Barrera
Eric J
EJ
Huang
Baidong
B
Hou
Barbara A
BA
Malynn
Boris
B
Reizis
Anthony
A
DeFranco
Lindsey A
LA
Criswell
Mary C
MC
Nakamura
Averil
A
Ma
D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003424:Crohn Disease / Q000235:genetics; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008206:Lymphatic Diseases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D013163:Splenomegaly / Q000235:genetics; D013167:Spondylitis, Ankylosing / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse