Journal Article

Peripheral education of the immune system by colonic commensal microbiota

Nutsch, Katherine, Peterson, Daniel A., Hsieh, Chyi-Song, Lathrop, Stephanie K., Bloom, Seth M., Rao, Sindhuja M., Lio, Chan-Wang, Stappenbeck, Thaddeus S., Santacruz, Nicole

2011

Overview

Learning to tolerate friendly bacteria Understanding how the immune system becomes tolerant to foreign antigens from commensal bacteria is a fundamental question, as breakdown of tolerance can result in unwanted responses such as inflammatory bowel disease. It has been suggested that tolerogenic regulatory T (T reg ) cells are generated in response to commensal bacteria, but there is little direct evidence to support this hypothesis. A study of the colonic T-cell antigen receptor repertoire of mice now shows that microbial antigens direct the generation of antigen-specific inducible T reg cells in the colon. Commensal-induced T reg cells seem to maintain mucosal tolerance and protect mice from colitis. 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 1 . 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 2 , 3 , 4 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2152/569/2495 / 692/698/1543/1565 / 692/698/2741/2135 / Animals / Bacteria / Bacterial proteins / Biological and medical sciences / Bone marrow / Colitis - immunology / Colitis - prevention & control / Colon - cytology / Colon - immunology / Colon - microbiology / Education / Flow cytometry / Fundamental and applied biological sciences. Psychology / Fundamental immunology / Humanities and Social Sciences / Immune system / Immune System - cytology / Immune System - immunology / Immune Tolerance - immunology / Immunity, Mucosal - immunology / Immunology / letter / Metagenome - immunology / Mice / Mice, Inbred C57BL / Mice, Transgenic / multidisciplinary / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Rodents / Science / Science (multidisciplinary) / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / Thymus Gland - cytology / Thymus Gland - immunology