Some papers just make no sense, especially when they appear in top journals, like Nature. What's going in editor's mind when they are green-lighting this type of research for publication?
Here is a new example for such paper. It was recently published in Nature (1). This study comes from Fiona Powrie's lab in UK. She became well-known for her studies of experimental colitis model in rats or mice upon adoptive transfer of naïve T cells (then, in 90's, called CD45RBhi). Her research is mainly focused on interplay between naïve T cells and Foxp3+ Tregs in colitis models.
This study is another variation of this approach.
First, the authors made an observation that gut associated Tregs express IL-33 receptor, while few Tregs from spleen or lymph nodes do.
Next, in vitro test showed that combination of IL-33 and TGFbeta-1 augments de novo Foxp3+ Treg differentiation (IL-33 alone had no effect).
To assess in vivo role of IL-33 signaling in Tregs, the authors first generated mixed bone marrow chimera mice using wild-type and IL-33 receptor-deficient marrow cells (also called ST2 -/-). Next, colitis was induced by combination of treatment with Helicobacter hepaticus and anti-IL-10R injection. Analysis of number of colonic Tregs derived from IL-33 receptor-deficient marrow cells (which can not respond to IL-33) were reduced 2-fold compared to wild-type Tregs. In addition, IL-33 receptor-deficient Tregs expressed reduced amount of Foxp3 compared to wild-type Tregs (1000 vs. 800 MFI).
Another set of in vivo experiments showed that IL-33 receptor-deficient Tregs were less potent in preventing colitis induction by naïve T cells. At 8 weeks post transfer, IL-33 receptor-deficient Tregs lost much of Foxp3 expression. Of note, in vitro IL-33 receptor-deficient Tregs were as potent as wild-type Tregs.
To connect this new observation with their previous studies about IL-23 and colitis, the authors showed that IL-23 blocks signaling by IL-33 in Tregs.
Finally, another set of in vivo adoptive transfer experiments into RAG1/IL-23R double knockout mice showed that in even in absence of IL-23 signaling in the host, IL-33 receptor-deficient Tregs were less potent in preventing colitis induction.
The data in Fig. 4d, however, are difficult to interpret. If IL-23 was blocking Tregs induction solely through IL-33 inhibition, absence of IL-23 should have had two fold outcome:
(a) induced much potent wild-type Tregs and
(b) IL-33 receptor-deficient Tregs should become more potent in preventing colitis
However, neither outcome has been observed, that is, in my opinion, very unusual and unexplainable result and questions the relevance or importance of all other data.