Colonic creatures are T_Reg teachers

Credit: CORBIS

Regulatory T (T_Reg) cells can arise both from developing T cells in the thymus and from naive T cells that are activated in a tolerogenic manner in the periphery. Thymic T_Reg cells recognize self-antigens, but the specificity of peripherally induced T_Reg cells is less well understood. This study suggests that most colonic T_Reg cells are specific for antigens derived from commensal bacteria and that each of us may possess a unique T_Reg cell repertoire that develops in response to our own microbiota.

each of us may possess a unique T_Reg cell repertoire that develops in response to our own microbiota

Previous work has shown that T_Reg cells with specificity for food antigens can be induced in the intestine. Commensal bacteria found in the intestine also promote T_Reg cell responses, but it has been unclear whether they do this mainly by inducing 'new' T_Reg cells with specificity for bacterial antigens or by expanding pre-existing T_Reg cell populations. To overcome the difficulty of assessing a fully polyclonal T cell receptor (TCR) repertoire, the authors used transgenic mice with a fixed TCR β-chain (these mice have a limited polyclonal TCR repertoire that is generated through Tcra gene rearrangements). They found that the TCRs expressed by effector or memory T cell populations were quite distinct from those expressed by T_Reg cells. Furthermore, T_Reg cells isolated from the spleen or peripheral lymph nodes used TCRs that were distinct from those found on colonic T_Reg cells. Thus, the TCR repertoire of colonic T_Reg cells appears to be shaped significantly by the local antigenic environment.

The authors next used an in vitro reporter system to show that cells expressing colonic T_Reg cell-associated TCRs (but not cells expressing other TCRs) could be activated via their TCRs when cultured with dendritic cells and autoclaved colonic contents from the transgenic mouse colony. Strikingly, the colonic T_Reg cell-derived TCRs could not be activated by colonic contents from germ-free mice or by colonic contents from mice sourced from a distinct mouse unit, unless these animals were first co-housed with the transgenic mouse colony. The colonic T_Reg cell TCRs showed specificity for antigens derived from distinct commensal species, including Parabacteroides spp., Bacteroides spp. and a previously uncharacterized Clostridiales species. More than half of the colonic T_Reg cell TCRs recognized colonic contents or bacterial isolates, suggesting that the TCR repertoire of T_Reg cells in the colon is largely skewed towards the recognition of bacterial antigens. Importantly, thymocytes that were transduced with the colonic T_Reg cell TCRs did not develop into T_Reg cells in the thymus, suggesting that these TCRs mainly mediate peripheral T_Reg cell development.

Finally, the authors showed that T cells with specificity for commensal bacteria can also promote disease. In mice with fixed TCR β-chains that had developed colitis as a result of another immune deficiency (in IL-2, IL-10 or TGFβ), TCRs previously associated with colonic T_Reg cells were instead expressed by effector T cells. When the effector cells expressing these TCRs were isolated and transferred to lymphocyte-deficient mice, the recipient animals developed colitis. Taken together, the authors' findings support the concept that when the intestinal environment fails to support T_Reg cell induction, components of the commensal microbiota can drive inflammatory disease.