Endogenous gut flora drives colonic RORγ+ Treg development

Foxp3 transcription factor drives development of specialized CD4 T cell subset called regulatory T cells (Tregs) which can protect against immune pathology. 20 years has passed since their re-discovery in 1995 and 10 years has passed since identification of Foxp3 transcription factor as a master regulator of Tregs induction. Still, there is not a single drug or cell therapy protocol approved that involves Tregs. Why? In my opinion it has to do with the fact that we don't how Tregs work.    

Here is another example published yesterday in journal Science. In this article, the authors led by Mathis-Benoist team have reported that colonic gut microbiota induced RORγ, a transcription factor commonly associated with Th17 cell development, in colonic Foxp3+ Tregs and its expression played a beneficial role in maintaining colonic tissue health.  

First, the authors showed that colonic but not spleen Foxp3+ T regs expressed RORγ transcription factor.

However, unlike RORγ+ inflammatory Th17 cells, RORγ+ Foxp3+ Tregs do not express IL-17.

Next, the authors showed that induction of colonic RORγ+ Foxp3+ Tregs was linked to multiple gut microbiota species (of note, the authors did not find any correlation between SCFA expression and RORγ+ Foxp3+ Tregs).

Finally, the authors showed that specific deletion of RORγ in colonic Foxp3+ T regs tipped the balance in favor of IL-17 and IFN-γ and worsened gut inflammation.

In summary, these results indicate that antagonistic transcription factors RORγ and Foxp3 co-expressed and are indeed necessary for proper functioning of tissue specific Tregs. This even more complicates already messy field.

David Usharauli