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.

Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice

Nature volume 449, pages 361–365 (2007)Cite this article

Abstract

The cytokine transforming growth factor-β (TGF-β) is an important negative regulator of adaptive immunity1,2,3. TGF-β is secreted by cells as an inactive precursor that must be activated to exert biological effects4, but the mechanisms that regulate TGF-β activation and function in the immune system are poorly understood. Here we show that conditional loss of the TGF-β-activating integrin αvβ8 on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of αvβ8 on dendritic cells, as mice lacking αvβ8 principally on dendritic cells develop identical immunological abnormalities as mice lacking αvβ8 on all leukocytes, whereas mice lacking αvβ8 on T cells alone are phenotypically normal. We further show that dendritic cells lacking αvβ8 fail to induce regulatory T cells (TR cells) in vitro, an effect that depends on TGF-β activity. Furthermore, mice lacking αvβ8 on dendritic cells have reduced proportions of TR cells in colonic tissue. These results suggest that αvβ8-mediated TGF-β activation by dendritic cells is essential for preventing immune dysfunction that results in inflammatory bowel disease and autoimmunity, effects that are due, at least in part, to the ability of αvβ8 on dendritic cells to induce and/or maintain tissue TR cells.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: (Vav1-cre)Itgb8 fl/fl mice develop age-related autoimmunity.
Figure 2: (Vav1-cre)Itgb8 fl/fl mice develop enhanced numbers of activated/memory T cells expressing IL-4 and IFN-γ, and increased serum IgE, IgG1 and IgA levels.
Figure 3: Mice lacking integrin β 8 on dendritic cells develop an identical immune phenotype to mice lacking β 8 integrin on all leukocytes.
Figure 4: β 8 -deficient dendritic cells fail to induce T R cells in vitro , and (CD11c-cre)Itgb8 fl/fl mice have reduced proportions of T R cells in colonic tissue.

Similar content being viewed by others

References

  1. Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992)

    Article  CAS  ADS  Google Scholar 

  2. Marie, J. C., Liggitt, D. & Rudensky, A. Y. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor. Immunity 25, 441–454 (2006)

    Article  CAS  Google Scholar 

  3. Li, M. O., Sanjabi, S. & Flavell, R. A. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455–471 (2006)

    Article  CAS  Google Scholar 

  4. Annes, J. P., Munger, J. S. & Rifkin, D. B. Making sense of latent TGFβ activation. J. Cell Sci. 116, 217–224 (2003)

    Article  CAS  Google Scholar 

  5. Huang, X. Z. et al. Inactivation of the integrin β6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J. Cell Biol. 133, 921–928 (1996)

    Article  CAS  Google Scholar 

  6. Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999)

    Article  CAS  Google Scholar 

  7. Mu, D. et al. The integrin αvβ8 mediates epithelial homeostasis through MT1–MMP-dependent activation of TGF-β1. J. Cell Biol. 157, 493–507 (2002)

    Article  CAS  Google Scholar 

  8. Yang, Z. et al. Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice. J. Cell Biol. 176, 787–793 (2007)

    Article  CAS  Google Scholar 

  9. Zhu, J. et al. β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129, 2891–2903 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Proctor, J. M., Zang, K., Wang, D., Wang, R. & Reichardt, L. F. Vascular development of the brain requires β8 integrin expression in the neuroepithelium. J. Neurosci. 25, 9940–9948 (2005)

    Article  CAS  Google Scholar 

  11. de Boer, J. et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur. J. Immunol. 33, 314–325 (2003)

    Article  CAS  Google Scholar 

  12. Gorelik, L. & Flavell, R. A. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000)

    Article  CAS  Google Scholar 

  13. Kim, B. G. et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441, 1015–1019 (2006)

    Article  CAS  ADS  Google Scholar 

  14. Bohr, U. R. et al. Prevalence and spread of enterohepatic Helicobacter species in mice reared in a specific-pathogen-free animal facility. J. Clin. Microbiol. 44, 738–742 (2006)

    Article  CAS  Google Scholar 

  15. Taylor, N. S., Xu, S., Nambiar, P., Dewhirst, F. E. & Fox, J. G. Enterohepatic Helicobacter species are prevalent in mice obtained from commercial and academic institutions in Asia, Europe, and North America. J. Clin. Microbiol. 45, 2166–2172 (2007)

    Article  CAS  Google Scholar 

  16. Whary, M. T. & Fox, J. G. Detection, eradication, and research implications of Helicobacter infections in laboratory rodents. Lab Anim. (NY) 35, 25–36 (2006)

    Article  Google Scholar 

  17. Strober, W., Fuss, I. & Mannon, P. The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 117, 514–521 (2007)

    Article  CAS  Google Scholar 

  18. Lee, P. P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001)

    Article  CAS  Google Scholar 

  19. Caton, M., L, 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  Google Scholar 

  20. Sakaguchi, S. et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212, 8–27 (2006)

    Article  CAS  Google Scholar 

  21. Chen, W. et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003)

    Article  CAS  Google Scholar 

  22. Nakamura, K. et al. TGF-β1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J. Immunol. 172, 834–842 (2004)

    Article  CAS  Google Scholar 

  23. Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005)

    Article  CAS  Google Scholar 

  24. Marie, J. C., Letterio, J. J., Gavin, M. & Rudensky, A. Y. TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061–1067 (2005)

    Article  CAS  Google Scholar 

  25. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005)

    Article  CAS  Google Scholar 

  26. Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003)

    Article  CAS  Google Scholar 

  27. Bluestone, J. A. & Tang, Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr. Opin. Immunol. 17, 638–642 (2005)

    Article  CAS  Google Scholar 

  28. Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K. & Flavell, R. A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2006)

    Article  CAS  Google Scholar 

  29. Lefrancois, L. & Lycke, N. Isolation of mouse small intestine intraepithelial lymphocytes, Peyer’s patch, and lamina propria cells. Curr. Protocols Immunol. Unit 3.19. doi: 10.1002/0471142735.im0319s17 (2001)

  30. Abe, M. et al. An assay for transforming growth factor-β using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal. Biochem. 216, 276–284 (1994)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Kioussis for providing the Vav1-Cre mice and A. Rudensky for providing the GFP–Foxp3 mice. This work was supported by grants from the National Heart, Lung and Blood Institute (to D.S.), the National Institute of Allergy and Infectious Diseases (to J.A.B and B.R.) and funds from the Sandler Program for Asthma Research (to B.R.). M.A.T. was the recipient of an American Lung Association Research Fellowship.

Author Contributions M.A.T. performed all of the experiments described and wrote most of the manuscript; B.R. generated the CD11c-Cre mice and contributed to the design and interpretation of studies using those mice; A.C.M. contributed to the studies of colonic inflammation, colonic TR cells and designed and performed all of the qPCR studies described; E.M. helped design, perform and interpret the in vitro TR cell induction assays; Q.T. helped to design, perform and interpret the studies analysing the nature of the immunological defects described; J.M.P. generated the conditional Itgb8 knockout mice and helped in the design and interpretation of genotyping assays and crosses to Cre-expressing lines; Y.W., X.B. and X.H. helped in the design, performance and interpretation of all of the studies of tissue morphology; L.F.R. oversaw the generation of the conditional Itgb8 knockout mice and contributed to the design and interpretation of studies using these animals; J.A.B. contributed to the design and interpretation of the studies characterizing the immunological abnormalities seen and analysing the contribution of TR cells; D.S. oversaw the design and interpretation of all studies described and oversaw writing of the manuscript.

Author information

Author notes

  1. Mark A. Travis

    Present address: Present address: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, A3051 Smith Building, Oxford Road, Manchester M13 9PT, UK.,

Authors and Affiliations

  1. Department of Medicine, Lung Biology Center, University of California San Francisco, 1550 4th Street, Room 545, San Francisco, California 94158, USA,

    Mark A. Travis, Andrew C. Melton, Yanli Wang, Xin Bernstein, Xiaozhu Huang & Dean Sheppard

  2. Department of Microbiology, Columbia University, 701 West 168th Street, Room 609, New York, New York 10032, USA,

    Boris Reizis

  3. Department of Medicine, Diabetes Center, 513 Parnassus Avenue, University of San Francisco, San Francisco, California 94143, USA,

    Emma Masteller, Qizhi Tang & Jeffrey A. Bluestone

  4. Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA,

    John M. Proctor & Louis F. Reichardt

Authors
  1. Mark A. Travis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Boris Reizis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew C. Melton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emma Masteller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qizhi Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John M. Proctor
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yanli Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xin Bernstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaozhu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Louis F. Reichardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jeffrey A. Bluestone
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dean Sheppard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dean Sheppard.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-7 with Legends. (PDF 680 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Travis, M., Reizis, B., Melton, A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007). https://doi.org/10.1038/nature06110

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06110

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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