Letter | Published:

Peripheral education of the immune system by colonic commensal microbiota

Nature volume 478, pages 250254 (13 October 2011) | Download Citation

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.

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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

Author notes

    • Stephanie K. Lathrop
    •  & Daniel A. Peterson

    Present addresses: Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana 59840, USA (S.K.L.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA (D.A.P.).

Affiliations

  1. Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St Louis, Missouri 63110, USA

    • Stephanie K. Lathrop
    • , Sindhuja M. Rao
    • , Katherine Nutsch
    • , Chan-Wang Lio
    • , Nicole Santacruz
    •  & Chyi-Song Hsieh
  2. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA

    • Seth M. Bloom
    •  & Thaddeus S. Stappenbeck
  3. Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, Nebraska 68583, USA

    • Daniel A. Peterson

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Chyi-Song Hsieh.

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DOI

https://doi.org/10.1038/nature10434

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