Peripheral education of the immune system by colonic commensal microbiota

SK Lathrop, SM Bloom, SM Rao, K Nutsch, CW Lio… - Nature, 2011 - nature.com
SK Lathrop, SM Bloom, SM Rao, K Nutsch, CW Lio, N Santacruz, DA Peterson
Nature, 2011nature.com
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) 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 …
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) 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 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.
nature.com