Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Chen, G., Shaw, M.H., Kim, Y.G. & Nunez, G. NOD-like receptors: role in innate immunity and inflammatory disease. Annu. Rev. Pathol. 4, 365–398 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Izcue, A., Coombes, J.L. & Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 27, 313–338 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Joffre, O., Nolte, M.A., Sporri, R. & Reis e Sousa, C. Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol. Rev. 227, 234–247 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Steinman, R.M. & Banchereau, J. Taking dendritic cells into medicine. Nature 449, 419–426 (2007).

    CAS  PubMed  Google Scholar 

  7. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Reis e Sousa, C. Dendritic cells in a mature age. Nat. Rev. Immunol. 6, 476–483 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Marshak-Rothstein, A. & Rifkin, I.R. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu. Rev. Immunol. 25, 419–441 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Steinman, R.M. & Nussenzweig, M.C. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl. Acad. Sci. USA 99, 351–358 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Opipari, A.W. Jr., Boguski, M.S. & Dixit, V.M. The A20 cDNA induced by tumor necrosis factor α encodes a novel type of zinc finger protein. J. Biol. Chem. 265, 14705–14708 (1990).

    CAS  PubMed  Google Scholar 

  14. Lee, E.G. et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 289, 2350–2354 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wertz, I.E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Boone, D.L. et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5, 1052–1060 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Hitotsumatsu, O. et al. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity 28, 381–390 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tavares, R.M. et al. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity 33, 181–191 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Turer, E.E. et al. Homeostatic MyD88-dependent signals cause lethal inflammation in the absence of A20. J. Exp. Med. 205, 451–464 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Graham, R.R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Musone, S.L. et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat. Genet. 40, 1062–1064 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Burton, P.R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Plenge, R.M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nair, R.P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet. 41, 199–204 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Elder, J.T. Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis. Genes Immun. 10, 201–209 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Trynka, G. et al. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-κB signalling. Gut 58, 1078–1083 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Caton, M.L., Smith-Raska, M.R. & Reizis, B. Notch-RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen. J. Exp. Med. 204, 1653–1664 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Birnberg, T. et al. Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity 29, 986–997 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Ohnmacht, C. et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Redmond, W.L. & Sherman, L.A. Peripheral tolerance of CD8 T lymphocytes. Immunity 22, 275–284 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Luckashenak, N. et al. Constitutive crosspresentation of tissue antigens by dendritic cells controls CD8+ T cell tolerance in vivo. Immunity 28, 521–532 (2008).

    CAS  PubMed  Google Scholar 

  33. Kearney, E.R., Pape, K.A., Loh, D.Y. & Jenkins, M.K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1, 327–339 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Hou, B., Reizis, B. & DeFranco, A.L. Toll-like receptors activate innate and adaptive immunity by using dendritic cell-intrinsic and -extrinsic mechanisms. Immunity 29, 272–282 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Travis, M.A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Taurog, J.D. et al. Inflammatory disease in HLA-B27 transgenic rats. Immunol. Rev. 169, 209–223 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Uhlig, H.H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Garrett, W.S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  40. D'Agostino, M.A. & Olivieri, I. Enthesitis. Best Pract. Res. Clin. Rheumatol. 20, 473–486 (2006).

    Article  PubMed  Google Scholar 

  41. Chen, M. et al. Dendritic cell apoptosis in the maintenance of immune tolerance. Science 311, 1160–1164 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Stranges, P.B. et al. Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity 26, 629–641 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Melillo, J.A. et al. Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function. J. Immunol. 184, 2638–2645 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Manicassamy, S. et al. Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329, 849–853 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Song, X.T. et al. A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression. Nat. Med. 14, 258–265 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Breckpot, K. et al. Attenuated expression of A20 markedly increases the efficacy of double-stranded RNA-activated dendritic cells as an anti-cancer vaccine. J. Immunol. 182, 860–870 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Werner, S.L. et al. Encoding NF-κB temporal control in response to TNF: distinct roles for the negative regulators IκBα and A20. Genes Dev. 22, 2093–2101 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hanada, T. et al. Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity. Immunity 19, 437–450 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Deane, J.A. et al. Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity 27, 801–810 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Adrianto, I. et al. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat. Genet. 43, 253–258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Melis, L. & Elewaut, D. Progress in spondylarthritis. Immunopathogenesis of spondyloarthritis: which cells drive disease? Arthritis Res. Ther. 11, 233 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Armaka, M. et al. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J. Exp. Med. 205, 331–337 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Keller, C., Webb, A. & Davis, J. Cytokines in the seronegative spondyloarthropathies and their modification by TNF blockade: a brief report and literature review. Ann. Rheum. Dis. 62, 1128–1132 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Archer, J.R. Ankylosing spondylitis, IgA, and transforming growth factors. Ann. Rheum. Dis. 54, 544–546 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Smith, J.A. et al. Gene expression analysis of macrophages derived from ankylosing spondylitis patients reveals interferondysregulation. Arthritis Rheum. 58, 1640–1649 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Duan, R., Leo, P., Bradbury, L., Brown, M.A. & Thomas, G. Gene expression profiling reveals a downregulation in immune-associated genes in patients with AS. Ann. Rheum. Dis. 69, 1724–1729 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Gianna Elena Hammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emre E Turer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kimberly E Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Celia J Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rommel Advincula
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shigeru Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julio Barrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eric J Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Baidong Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Barbara A Malynn
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Boris Reizis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anthony DeFranco
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lindsey A Criswell
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mary C Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Averil Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Averil Ma.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 1961 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2135

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing