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Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis

Nature Immunology volume 12, pages 1184–1193 (2011)Cite this article

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Abstract

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.

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Figure 1: A20 prevents spontaneous activation of DCs in A20fl/flCd11c-Cre mice.
Figure 2: A20-deficient DCs induce the population expansion of myeloid and lymphoid cells.
Figure 3: A20 expression in DCs is needed to prevent aberrant T cell activation.
Figure 4: MyD88-independent signals trigger DC activation and drive aberrant T cell activation in A20fl/flCd11c-Cre mice.
Figure 5: MyD88-dependent signals in DCs drive the expansion of T cell populations in A20fl/flCd11c-Cre mice.
Figure 6: A20 function in DCs preserves intestinal homeostasis.
Figure 7: A20-deficient DCs activate naive T cells and drive T cell–mediated colitis.
Figure 8: A20fl/flCd11c-Cre mice spontaneously develop arthritic disease with pathologies similar to human IBD-associated arthritis.

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Acknowledgements

This work was supported by the US National Institutes of Health (A.M.), The Crohn's and Colitis Foundation of America (A.M. and S.O.), The Damon Runyon Cancer Research Foundation (G.E.H.), the Kenneth Rainin Foundation and the UCSF Liver Center and the Wellcome Trust (076113 and 085475 to the Wellcome Trust Case-Control Consortium). A full list of investigators who contributed to this work is available from the Wellcome Trust Case-Control Consortium website.

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Authors and Affiliations

  1. Department of Medicine, University of California at San Francisco, San Francisco, California, USA

    Gianna Elena Hammer, Emre E Turer, Kimberly E Taylor, Celia J Fang, Rommel Advincula, Shigeru Oshima, Julio Barrera, Eric J Huang, Barbara A Malynn, Lindsey A Criswell, Mary C Nakamura & Averil Ma

  2. San Francisco Veterans Affairs Medical Center, San Francisco, California, USA

    Celia J Fang

  3. Department of Pathology, University of California at San Francisco, San Francisco, California, USA

    Eric J Huang & Mary C Nakamura

  4. Pathology Service, VA Medical Center, San Francisco, California, USA

    Eric J Huang & Mary C Nakamura

  5. Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA

    Baidong Hou & Anthony DeFranco

  6. Department of Microbiology and Immunology, Columbia University, New York, New York, USA

    Boris Reizis

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Contributions

G.E.H. designed and did experiments with A20fl/flCd11c-Cre and related mice; E.E.T. and B.A.M. generated A20fl/flCd11c-Cre mice; E.E.T. initiated analyses of A20fl/flCd11c-Cre mice; B.R. generated Cd11c-Cre mice; B.H. and A.D. generated Myd88fl/fl mice; S.O. assisted with colitis experiments; K.E.T. and L.A.C. did genetic analyses of A20 SNPs with data from the Wellcome Trust; C.J.F., E.J.H. and M.C.N. did micro–computed tomography scans and histological analyses of arthritic joints; R.A. and J.B. assisted with breeding, genotyping and radiation chimera experiments; A.M. directed the study; and A.M. and G.E.H., with input from B.A.M., wrote the manuscript.

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Correspondence to Averil Ma.

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Hammer, G., Turer, E., Taylor, K. et al. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol 12, 1184–1193 (2011). https://doi.org/10.1038/ni.2135

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