Peripheral education of the immune system by colonic commensal microbiota

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(2-4). 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.