exTh17 cells cannot go unnoticed

Interleukin-17 (IL-17) is clinically relevant target molecule. T helper subset called Th17 are thought to produce large amounts of IL-17. Paradoxically, IL-17 is implicated in several human diseases such as psoriasis and inflammatory bowel disease (IBD), as well as autoimmune arthritis and autoimmune encephalitis. So, scientists are naturally very curious to understand Th17 subset's biology.

This new paper in journal Nature provided half-hearted data suggesting that Th17 cells undergo trans-differentiation into "regulatory T cells".    

Initially when I saw the article's title and read its abstract I thought it was about Th17-Foxp3 conversion since the authors used such term such as "regulatory T cells" which ordinarily refers to Foxp3+ CD4 T cells. However, it turned out results had nothing to do with Foxp3 T cells. 

Initially, the authors showed that in both steady state or during α-CD3 induced inflammation, CD4 T cells expressing IL-17 could lose its expression and instead up-regulate IL-10 (called here Tr1^exTh17 cells). However, for some reason the authors failed to show IL-10 expression level on CD4 T cells maintaining IL-17 expression (this could have been useful control). In addition, the authors did not discuss or show whether presence of two different types of IL-17A gene in a single cell could affect their individual expression maximum.

Next, the authors showed that Tr1^exTh17 cells could prevent colitis development in RAG KO hosts when co-transferred with pathogenic Th17 cells.

The authors also showed that anti-CD3 injection in mice immunized 35 days earlier with brain protein MOG  could induce Tr1^exTh17 cells.

These data so far suggest that non-physiological stimulation of T cells with α-CD3 antibody induced down-regulation of IL-17 and up-regulation of IL-10 in a subset of activated CD4 T cells. Whether these Tr1^exTh17 cells are derived from bona fide Th17 is not clear.   

Next, the authors used two disease models.  In Th2 dominant disease model of Nippostrongylus Brasiliensis, the authors observed the development of Tr1^exTh17 only after 2nd round of re-infection.

In a second Th17 dominant disease model of Staphylococcus Aureus, however, the authors conclusions that there is Tr1^exTh17 cell development is premature, in my view. The authors simply did not apply proper flow cytometry gating in this case.

In summary, in my view the correct interpretation of the data in this paper is following:

1.  Tr1^exTh17 can develop from activated T cells previously expressing IL-17, however those cells may not be bona fide Th17 cells.  

2. Effect of non-physiological stimuli such as α-CD3 antibody on T cells differentiation may lead to incorrect conclusions.

3. Based on results, in Staphylococcus Aureus model, there is no or very limited trans-differentiation of exIL-17 expressing T cells into Tr1^exTh17.   

Shortly, the major flaw in this paper is its heavy focus on gene-modified mice (on technology) rather than on biology.    

David Usharauli