Role reversal

Credit: S.Bradbrook/NPG

CD4⁺ T helper (T_H) cells differentiate into different specialized subsets depending on their circumstances. Increasing evidence suggests that this process is more flexible than originally thought. This study shows that T_H17 cells transdifferentiate into T regulatory type 1 (T_R1) cells and contribute to the resolution of inflammation in mice.

The authors used reporter mice to track the fate of T_H17 cells in vivo: T cells that have expressed high levels of interleukin-17A (IL-17A) were permanently marked with yellow fluorescent protein and any subsequent expression of the regulatory T cell markers IL-10 and forkhead box P3 (FOXP3) was also tagged and could be measured directly ex vivo. In the steady state, approximately half of all mouse intestinal CD4⁺ T cells that had expressed IL-17A no longer expressed this cytokine — the authors referred to these cells as ex-T_H17 cells. Some intestinal ex-T_H17 cells expressed IL-10 and some expressed FOXP3. Following a self-limiting inflammatory response induced by injection of CD3-specific monoclonal antibody, an expansion of the intestinal T_H17 cell population was followed by an increase in the number of ex-T_H17 cells expressing high levels of IL-10, with a few of these cells co-expressing IL-10 and FOXP3. The IL-10⁺ ex-T_H17 cells more closely resembled T_R1 cells than T_H17 cells (that is, they were LAG3⁺CCR6⁻RORγt^low).

ex-T_H17 T_R1 cells were able to prevent T_H17 cell-mediated colitis

Using a modified version of the mouse model in which IL-17A expression was induced by tamoxifen, the authors showed that T_H17 cells also convert into T_R1 cells during an immune response. Comparison of the gene signatures of T_H17 cells and T_R1 cells confirmed that the conversion of T_H17 cells into T_R1 cells is associated with transcriptional reprogramming — a process known as transdifferentiation. In support of this, ex-T_H17 T_R1 cells were able to prevent T_H17 cell-mediated colitis.

The conversion of T_H17 cells into T_R1 cells seems to be a common phenomenon: transdifferentiation was observed during transient inflammation in the intestine, during secondary infection with the worm Nippostrongylus brasiliensis and during an acute infection with the bacterium Staphylococcus aureus. Interestingly, during the primary immune response to N. brasiliensis, T_H17 cells lost IL-17A expression and gained a T_H2-type phenotype. But when the mice were re-infected with N. brasiliensis, T_H17 cells converted into T_R1 cells, suggesting that this conversion is a physiological mechanism to limit potentially destructive immune responses.

Finally, the authors investigated the pathways that drive this transdifferentiation. They found that transforming growth factor-β1 (TGFβ1) promoted the conversion of T_H17 cells into T_R1 cells in vitro, with the downstream signalling molecule SMAD3 appearing to have an essential role. In addition, TGFβ1 induces the expression of aryl hydrocarbon receptor (AHR), which is known to promote Il10 transactivation. Accordingly, the conversion of intestinal T_H17 cells into T_R1 cells was enhanced by the addition of AHR ligands to T cell cultures containing TGFβ1.

This study opens up potential new therapeutic opportunities for resolving inflammatory disease by forcing formerly pathogenic T_H17 cells to adopt an anti-inflammatory state.