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:

Plasticity of TH17 cells in Peyer's patches is responsible for the induction of T cell–dependent IgA responses

Nature Immunology volume 14, pages 372–379 (2013)Cite this article

Subjects

Abstract

Intestinal Peyer's patches are essential lymphoid organs for the generation of T cell–dependent immunoglobulin A (IgA) for gut homeostasis. Through the use of interleukin 17 (IL-17) fate-reporter mice, we found here that endogenous cells of the TH17 subset of helper T cells in lymphoid organs of naive mice 'preferentially' homed to the intestines and were maintained independently of IL-23. In Peyer's patches, such TH17 cells acquired a follicular helper T cell (TFH cell) phenotype and induced the development of IgA-producing germinal center B cells. Mice deficient in TH17 cells failed to generate antigen-specific IgA responses, which provides evidence that TH17 cells are the crucial subset required for the production of high-affinity T cell–dependent IgA.

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: 'Preferential' migration of eYFP+ TH17 cells into gut-associated tissues.
Figure 2: Reprogramming of TH17 cell profiles to a TFH cell phenotype in PP.
Figure 3: IL-23 is dispensable for the homeostatic maintenance and plasticity of intestinal TH17 cells.
Figure 4: Induction of B cell IgA by TH17 cells.
Figure 5: Analysis of Tcra−/− mice given transfer of eYFP+ TH17 cells together with CD25hi (Foxp3+) Treg cells.
Figure 6: Cholera toxin–specific IgA response in Il17aCreR26ReYFP mice.
Figure 7: The cholera toxin–specific IgA response requires TH17 cells.

Similar content being viewed by others

References

  1. Shulzhenko, N. et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat. Med. 17, 1585–1593 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Castigli, E. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat. Genet. 37, 829–834 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Ivanov, I.I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Talham, G.L., Jiang, H.Q., Bos, N.A. & Cebra, J.J. Segmented filamentous bacteria are potent stimuli of a physiologically normal state of the murine gut mucosal immune system. Infect. Immun. 67, 1992–2000 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 28, 243–273 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Macpherson, A.J., McCoy, K.D., Johansen, F.E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11–22 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Fritz, J.H. et al. Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 481, 199–203 (2012).

    Article  CAS  Google Scholar 

  9. Tezuka, H. et al. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448, 929–933 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Bergqvist, P., Stensson, A., Lycke, N.Y. & Bemark, M. T cell-independent IgA class switch recombination is restricted to the GALT and occurs prior to manifest germinal center formation. J. Immunol. 184, 3545–3553 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. McGeachy, M.J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat. Immunol. 10, 314–324 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255–263 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Esplugues, E. et al. Control of TH17 cells occurs in the small intestine. Nature 475, 514–518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vinuesa, C.G. & Cyster, J.G. How T cells earn the follicular rite of passage. Immunity 35, 671–680 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Kawamoto, S. et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 336, 485–489 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Peters, A. et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986–996 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Linterman, M.A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Eberl, G. et al. An essential function for the nuclear receptor RORγ(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5, 64–73 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. 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  PubMed  Google Scholar 

  23. Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Kurebayashi, S. et al. Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Natl. Acad. Sci. USA 97, 10132–10137 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lee, Y.K., Mukasa, R., Hatton, R.D. & Weaver, C.T. Developmental plasticity of Th17 and Treg cells. Curr. Opin. Immunol. 21, 274–280 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Lu, K.T. et al. Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity 35, 622–632 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kinugasa, T., Sakaguchi, T., Gu, X. & Reinecker, H.C. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118, 1001–1011 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Ishigame, H. et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108–119 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Codarri, L. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 12, 560–567 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. O'Connor, W. Jr., Zenewicz, L.A. & Flavell, R.A. The dual nature of TH17 cells: shifting the focus to function. Nat. Immunol. 11, 471–476 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Cao, A.T., Yao, S., Gong, B., Elson, C.O. & Cong, Y. Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J. Immunol. 189, 4666–4673 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Suzuki, K. et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl. Acad. Sci. USA 101, 1981–1986 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. King, I.L. & Mohrs, M. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 206, 1001–1007 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reinhardt, R.L., Liang, H.E. & Locksley, R.M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10, 385–393 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zaretsky, A.G. et al. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206, 991–999 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  37. Nakayamada, S. et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35, 919–931 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Choi, Y.S. et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 932–946 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kerfoot, S.M. et al. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity 34, 947–960 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kitano, M. et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34, 961–972 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Cong, Y., Feng, T., Fujihashi, K., Schoeb, T.R. & Elson, C.O. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl. Acad. Sci. USA 106, 19256–19261 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Komatsu, N. et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. USA 106, 1903–1908 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wan, Y.Y. & Flavell, R.A. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc. Natl. Acad. Sci. USA 102, 5126–5131 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhou, L. et al. TGF-beta-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, N.S. et al. Divergent transcriptional programming of class-specific B cell memory by T-bet and RORα. Nat. Immunol. 13, 604–611 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Philpott, K.L. et al. Lymphoid development in mice congenitally lacking T cell receptor αβ-expressing cells. Science 256, 1448–1452 (1992).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Cua (Merck Research Laboratories) for the Il23a−/− mouse strain; A. Hayday (King's College London) for Tcra−/− mice; A. Zal and T. Zal (MD Anderson) for advice on microscopy of PP; the flow facility of the Medical Research Council National Institute for Medical Research for cell sorting; and Biological Services of the Medical Research Council National Institute for Medical Research for the breeding and maintenance of mouse strains. Supported by The European Mouse Mutant Archive, the European Union Framework Programme 7 Capacities Specific Program (for axenization), Medical Research Council UK (U117512792), Deutsche Forschungsgemeinschaft (TU 316/1-1 to. J.-E.T.) and Boehringer Ingelheim Fonds (M.V.).

Author information

Author notes

  1. Keiji Hirota

    Present address: Present address: Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.,

  2. Jan-Eric Turner and Matteo Villa: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, Mill Hill, London, UK

    Keiji Hirota, Jan-Eric Turner, Matteo Villa, João H Duarte & Brigitta Stockinger

  2. Department of Lymphocyte Physiology, Instituto Gulbenkian De Ciência, Oeiras, Portugal

    Jocelyne Demengeot

  3. III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Germany

    Oliver M Steinmetz

Authors
  1. Keiji Hirota
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan-Eric Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matteo Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. João H Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jocelyne Demengeot
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Oliver M Steinmetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Brigitta Stockinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.H. and B.S. conceived of the project, designed the experiments and wrote the paper; K.H. did most of the experiments; M.V., J-E.T. and J.H.D. did specific experiments; J.D. established the germ-free colony of reporter mice; and O.M.S. supplied bone marrow from Rorc−/− mice.

Corresponding author

Correspondence to Brigitta Stockinger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2 (PDF 2536 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hirota, K., Turner, JE., Villa, M. et al. Plasticity of TH17 cells in Peyer's patches is responsible for the induction of T cell–dependent IgA responses. Nat Immunol 14, 372–379 (2013). https://doi.org/10.1038/ni.2552

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2552

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