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.

Peripheral education of the immune system by colonic commensal microbiota

Abstract

The instruction of the immune system to be tolerant of self, thereby preventing autoimmunity, is facilitated by the education of T cells in a specialized organ, the thymus, in which self-reactive cells are either eliminated or differentiated into tolerogenic Foxp3+ regulatory T (Treg) cells1. However, it is unknown whether T cells are also educated to be tolerant of foreign antigens, such as those from commensal bacteria, to prevent immunopathology such as inflammatory bowel disease2,3,4. Here we show that encounter with commensal microbiota results in the peripheral generation of Treg cells rather than pathogenic effectors. We observed that colonic Treg cells used T-cell antigen receptors (TCRs) different from those used by Treg cells in other locations, implying an important role for local antigens in shaping the colonic Treg-cell population. Many of the local antigens seemed to be derived from commensal bacteria, on the basis of the in vitro reactivity of common colon Treg TCRs. These TCRs did not facilitate thymic Treg-cell development, implying that many colonic Treg cells arise instead by means of antigen-driven peripheral Treg-cell development. Further analysis of two of these TCRs by the creation of retroviral bone marrow chimaeras and a TCR transgenic line revealed that microbiota indigenous to our mouse colony was required for the generation of colonic Treg cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo Treg-cell development and instead become effector cells, they have the potential to induce colitis, as evidenced by adoptive transfer studies. These results suggest that the efficient peripheral generation of antigen-specific populations of Treg cells in response to an individual’s microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota.

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

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

Figure 1: The colonic T reg TCR repertoire is unique.
Figure 2: In vitro reactivity of colonic T reg TCRs to colonic contents and bacterial isolates.
Figure 3: Colonic T reg TCRs facilitate thymic T reg -cell development poorly, if at all.
Figure 4: Pathogenic potential of colonic T reg TCRs.

References

  1. Josefowicz, S. Z. & Rudensky, A. Control of regulatory T cell lineage commitment and maintenance. Immunity 30, 616–625 (2009)

    Article  CAS  Google Scholar 

  2. Belkaid, Y. & Tarbell, K. Regulatory T cells in the control of host–microorganism interactions. Annu. Rev. Immunol. 27, 551–589 (2009)

    Article  CAS  Google Scholar 

  3. Barnes, M. J. & Powrie, F. Regulatory T cells reinforce intestinal homeostasis. Immunity 31, 401–411 (2009)

    Article  CAS  Google Scholar 

  4. Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host–bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005)

    Article  ADS  Google Scholar 

  5. Min, B. et al. Gut flora antigens are not important in the maintenance of regulatory T cell heterogeneity and homeostasis. Eur. J. Immunol. 37, 1916–1923 (2007)

    Article  CAS  Google Scholar 

  6. Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010)

    Article  ADS  CAS  Google Scholar 

  7. Singh, B. et al. Control of intestinal inflammation by regulatory T cells. Immunol. Rev. 182, 190–200 (2001)

    Article  CAS  Google Scholar 

  8. Curotto de Lafaille, M. A. et al. Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 29, 114–126 (2008)

    Article  CAS  Google Scholar 

  9. Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 Treg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007)

    Article  CAS  Google Scholar 

  10. Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010)

    Article  ADS  CAS  Google Scholar 

  11. 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 

  12. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007)

    Article  ADS  CAS  Google Scholar 

  13. Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced Treg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007)

    Article  CAS  Google Scholar 

  14. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011)

    Article  ADS  CAS  Google Scholar 

  15. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011)

    Article  ADS  CAS  Google Scholar 

  16. 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  ADS  CAS  Google Scholar 

  17. Hsieh, C.-S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004)

    Article  CAS  Google Scholar 

  18. Pacholczyk, R., Ignatowicz, H., Kraj, P. & Ignatowicz, L. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 25, 249–259 (2006)

    Article  CAS  Google Scholar 

  19. Wong, J. et al. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J. Immunol. 178, 7032–7041 (2007)

    Article  CAS  Google Scholar 

  20. Lathrop, S. K., Santacruz, N. A., Pham, D., Luo, J. & Hsieh, C. S. Antigen-specific peripheral shaping of the natural regulatory T cell population. J. Exp. Med. 205, 3105–3117 (2008)

    Article  CAS  Google Scholar 

  21. Ise, W. et al. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nature Immunol. 11, 129–135 (2010)

    Article  CAS  Google Scholar 

  22. Bloom, S. M. et al. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 9, 390–403 (2011)

    Article  CAS  Google Scholar 

  23. Bautista, J. L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nature Immunol. 10, 610–617 (2009)

    Article  CAS  Google Scholar 

  24. Leung, M. W., Shen, S. & Lafaille, J. J. TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes. J. Exp. Med. 206, 2121–2130 (2009)

    Article  CAS  Google Scholar 

  25. Nishio, J., Feuerer, M., Wong, J., Mathis, D. & Benoist, C. Anti-CD3 therapy permits regulatory T cells to surmount T cell receptor-specified peripheral niche constraints. J. Exp. Med. 207, 1879–1889 (2010)

    Article  CAS  Google Scholar 

  26. Thornton, A. M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010)

    Article  CAS  Google Scholar 

  27. Hsieh, C. S., Zheng, Y., Liang, Y., Fontenot, J. D. & Rudensky, A. Y. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nature Immunol. 7, 401–410 (2006)

    Article  CAS  Google Scholar 

  28. Lin, W. et al. Regulatory T cell development in the absence of functional Foxp3. Nature Immunol. 8, 359–368 (2007)

    Article  CAS  Google Scholar 

  29. Schorle, H., Holtschke, T., Hunig, T., Schimpl, A. & Horak, I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621–624 (1991)

    Article  ADS  CAS  Google Scholar 

  30. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993)

    Article  CAS  Google Scholar 

  31. 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 

  32. Magurran, A. E. Ecological Diversity and its Measurement (Princeton Univ. Press, 1988)

    Book  Google Scholar 

  33. Haxhinasto, S., Mathis, D. & Benoist, C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565–574 (2008)

    Article  CAS  Google Scholar 

  34. Holst, J., Vignali, K. M., Burton, A. R. & Vignali, D. A. Rapid analysis of T-cell selection in vivo using T cell-receptor retrogenic mice. Nature Methods 3, 191–197 (2006)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Murphy, T. Egawa, Y. Zheng, J. Scott-Browne, J. Fontenot and S. Wetzel for discussion and reading of the manuscript; A. Kau and J. Gordon for discussions and generation of germ-free animals; N. P. Malvin for assistance with bacteriology; and J. Hunn for technical assistance. C.S.H. and co-workers are funded by the National Institute of Allergy and Infectious Diseases and the Burroughs-Wellcome Fund. S.M.B. was supported by National Institutes of Health training grant 5T32AI0071632.

Author information

Authors and Affiliations

Authors

Contributions

S.K.L., S.R., K.N. and N.S. performed most of the experiments. S.M.B. designed and performed the bacteriology. C.W.L. developed and assisted with the intrathymic transfer experiments. D.P. and T.S. were involved in study design. S.K.L. and C.S.H. designed the experiments and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Chyi-Song Hsieh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-16 with legends. (PDF 1528 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lathrop, S., Bloom, S., Rao, S. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011). https://doi.org/10.1038/nature10434

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10434

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

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