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.

  • Letter
  • Published:

ATP drives lamina propria TH17 cell differentiation

Nature volume 455, pages 808–812 (2008)Cite this article

Abstract

Interleukin (IL)-17-producing CD4+ T lymphocytes (TH17 cells) constitute a subset of T-helper cells involved in host defence and several immune disorders1,2. An intriguing feature of TH17 cells is their selective and constitutive presence in the intestinal lamina propria3. Here we show that adenosine 5′-triphosphate (ATP) that can be derived from commensal bacteria activates a unique subset of lamina propria cells, CD70highCD11clow cells, leading to the differentiation of TH17 cells. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria TH17 cells, compared to specific-pathogen-free mice. Systemic or rectal administration of ATP into these germ-free mice results in a marked increase in the number of lamina propria TH17 cells. A CD70highCD11clow subset of the lamina propria cells expresses TH17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-factor-β-activating integrin-αV and -β8, in response to ATP stimulation, and preferentially induces TH17 differentiation of co-cultured naive CD4+ T cells. The critical role of ATP is further underscored by the observation that administration of ATP exacerbates a T-cell-mediated colitis model with enhanced TH17 differentiation. These observations highlight the importance of commensal bacteria and ATP for TH17 differentiation in health and disease, and offer an explanation of why TH17 cells specifically present in the intestinal lamina propria.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Administration of ATP leads to a marked increase in lamina propria T H 17 cells in otherwise T H 17-lacking germ-free mice.
Figure 2: ATP induces differentiation of naive CD4 + T cells into T H 17 cells.
Figure 3: A unique subset of lamina propria CD11c + cells express P2X and P2Y receptors.
Figure 4: Treatment with ATP exacerbates experimental colitis induced by adoptive transfer of naive CD4 + T cells.

Similar content being viewed by others

References

  1. Weaver, C. T., Hatton, R. D., Mangan, P. R. & Harrington, L. E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007)

    Article  CAS  Google Scholar 

  2. Bettelli, E., Oukka, M. & Kuchroo, V. K. TH-17 cells in the circle of immunity and autoimmunity. Nature Immunol. 8, 345–350 (2007)

    Article  CAS  Google Scholar 

  3. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006)

    Article  CAS  Google Scholar 

  4. Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006)

    Article  CAS  Google Scholar 

  5. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007)

    Article  ADS  CAS  Google Scholar 

  6. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967–974 (2007)

    Article  CAS  Google Scholar 

  8. Cho, J. H. & Weaver, C. T. The genetics of inflammatory bowel disease. Gastroenterology 133, 1327–1339 (2007)

    Article  CAS  Google Scholar 

  9. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006)

    Article  CAS  Google Scholar 

  10. Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006)

    Article  ADS  CAS  Google Scholar 

  11. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006)

    Article  ADS  CAS  Google Scholar 

  12. Cua, D. J. & Kastelein, R. A. TGF-β, a ‘double agent’ in the immune pathology war. Nature Immunol. 7, 557–559 (2006)

    Article  CAS  Google Scholar 

  13. Chang, S. Y. et al. Colonic patches direct the cross-talk between systemic compartments and large intestine independently of innate immunity. J. Immunol. 180, 1609–1618 (2008)

    Article  CAS  Google Scholar 

  14. Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nature Rev. Immunol. 3, 63–72 (2003)

    Article  CAS  Google Scholar 

  15. North, R. A. Molecular physiology of P2X receptors. Physiol. Rev. 82, 1013–1067 (2002)

    Article  CAS  Google Scholar 

  16. Schnurr, M. et al. Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway. Blood 105, 1582–1589 (2005)

    Article  CAS  Google Scholar 

  17. Khakh, B. S. & North, R. A. P2X receptors as cell-surface ATP sensors in health and disease. Nature 442, 527–532 (2006)

    Article  ADS  CAS  Google Scholar 

  18. Idzko, M. et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nature Med. 13, 913–919 (2007)

    Article  CAS  Google Scholar 

  19. Ivanova, E. P., Alexeeva, Y. V., Pham, D. K., Wright, J. P. & Nicolau, D. V. ATP level variations in heterotrophic bacteria during attachment on hydrophilic and hydrophobic surfaces. Int. Microbiol. 9, 37–46 (2006)

    CAS  PubMed  Google Scholar 

  20. Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunol. 2, 361–367 (2001)

    Article  CAS  Google Scholar 

  21. Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005)

    Article  ADS  CAS  Google Scholar 

  22. Travis, M. A. et al. Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007)

    Article  ADS  CAS  Google Scholar 

  23. Takeda, K. et al. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 161, 4652–4660 (1998)

    CAS  PubMed  Google Scholar 

  24. Iwasaki, A. Mucosal dendritic cells. Annu. Rev. Immunol. 25, 381–418 (2007)

    Article  CAS  Google Scholar 

  25. Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007)

    Article  CAS  Google Scholar 

  26. Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nature Immunol. 8, 1086–1094 (2007)

    Article  CAS  Google Scholar 

  27. Hendriks, J. et al. CD27 is required for generation and long-term maintenance of T cell immunity. Nature Immunol. 1, 433–440 (2000)

    Article  CAS  Google Scholar 

  28. Zaba, L. C. et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 204, 3183–3194 (2007)

    Article  CAS  Google Scholar 

  29. Leach, M. W., Bean, A. G., Mauze, S., Coffman, R. L. & Powrie, F. Inflammatory bowel disease in C.B-17 scid mice reconstituted with the CD45RBhigh subset of CD4+ T cells. Am. J. Pathol. 148, 1503–1515 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008)

    Article  ADS  CAS  Google Scholar 

  31. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640–643 (2003)

    Article  ADS  CAS  Google Scholar 

  32. Mizoguchi, E. et al. Colonic epithelial functional phenotype varies with type and phase of experimental colitis. Gastroenterology 125, 148–161 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Iwasaki and N. Tsuji for discussion, M. H. Jang, H. Ohno, H. Yamane, M. Yoshida and H. Shiomi for technical advice and reagents, and J. Borst for CD27-deficient mice. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labour and Welfare, the Osaka Foundation for the Promotion of Clinical Immunology, the Ichiro Kanehara Foundation, Sumitomo Foundation, Senri Life Science Foundation and the Naito Foundation.

Author Contributions K.H. conceived the research, planned experiments and analyses and wrote the paper; K.A. and J.N. largely conducted experiments; T.S. performed some of the experiments; Y.U., M.Y., M.O., H.Y., N.I. and R.E. provided key materials; and K.T. oversaw the whole project.

Author information

Author notes

  1. Koji Atarashi and Junichi Nishimura: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan ,

    Koji Atarashi, Junichi Nishimura, Masahiro Yamamoto, Kenya Honda & Kiyoshi Takeda

  2. Yakult Central Institute for Microbiological Research, Yaho 1796, Kunitachi, Tokyo 186-8650, Japan ,

    Tatsuichiro Shima, Yoshinori Umesaki & Masaharu Onoue

  3. WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan

    Masahiro Yamamoto, Kenya Honda & Kiyoshi Takeda

  4. Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan,

    Hideo Yagita

  5. Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan,

    Naoto Ishii

  6. Department of Cell Physiology and Pharmacology, Henry Wellcome Building 2/59b, University of Leicester, Leicester LE1 9HN, UK

    Richard Evans

Authors
  1. Koji Atarashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junichi Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsuichiro Shima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshinori Umesaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masahiro Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masaharu Onoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hideo Yagita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naoto Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Richard Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kenya Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kiyoshi Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kenya Honda or Kiyoshi Takeda.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-12 with Legends. (PDF 4600 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Atarashi, K., Nishimura, J., Shima, T. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008). https://doi.org/10.1038/nature07240

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07240

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