TY - JOUR
T1 - Peripheral education of the immune system by colonic commensal microbiota
AU - Lathrop, Stephanie K.
AU - Bloom, Seth M.
AU - Rao, Sindhuja M.
AU - Nutsch, Katherine
AU - Lio, Chan Wang
AU - Santacruz, Nicole
AU - Peterson, Daniel A.
AU - Stappenbeck, Thaddeus S.
AU - Hsieh, Chyi Song
N1 - Funding Information:
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.
PY - 2011/10/13
Y1 - 2011/10/13
N2 - 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 (T reg) cells. 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 disease. Here we show that encounter with commensal microbiota results in the peripheral generation of T reg cells rather than pathogenic effectors. We observed that colonic T reg cells used T-cell antigen receptors (TCRs) different from those used by T reg cells in other locations, implying an important role for local antigens in shaping the colonic T reg-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 T reg TCRs. These TCRs did not facilitate thymic T reg-cell development, implying that many colonic T reg cells arise instead by means of antigen-driven peripheral T reg-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 T reg cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo T reg-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 T reg 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.
AB - 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 (T reg) cells. 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 disease. Here we show that encounter with commensal microbiota results in the peripheral generation of T reg cells rather than pathogenic effectors. We observed that colonic T reg cells used T-cell antigen receptors (TCRs) different from those used by T reg cells in other locations, implying an important role for local antigens in shaping the colonic T reg-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 T reg TCRs. These TCRs did not facilitate thymic T reg-cell development, implying that many colonic T reg cells arise instead by means of antigen-driven peripheral T reg-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 T reg cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo T reg-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 T reg 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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U2 - 10.1038/nature10434
DO - 10.1038/nature10434
M3 - Article
C2 - 21937990
AN - SCOPUS:80054020840
SN - 0028-0836
VL - 478
SP - 250
EP - 254
JO - Nature
JF - Nature
IS - 7368
ER -