Just read another paper about Foxp3+ Tregs published in journal Immunity. Not clear what to make out of it. It came from Christophe Benoist and Diane Mathis lab, both wellknown immunologists, but it feels if it was done by non-immunologist. It does have Amy J. Wagers as a co-authors. She is known for her studies of stem cells.
So, the basic premise of this study is that aging decreases muscle regeneration [after injury] due to failure to recruit IL-33 responsive Tregs.
Now, how does one test this hypothesis? I will highlight what is good in this paper and what is missing. Initially, the authors showed that in old mice muscle injury (cryo-injury or by toxin) does not attracts as much Tregs as in young mice. Strangely, Tregs recruitment within injured muscle tissue was examined using anti-Foxp3 antibody rather more widely accepted model of Foxp3 reporter mice [which they indicated in methods section they had].
Next, the authors found that cytokine IL-33 was up-regulated in injured muscle tissue (young mouse).
Correspondingly, Tregs recruited and enriched within injured muscle tissue expressed IL-33 receptor called ST2.
Next, the authors speculated that there was maybe some connection between IL-33 responsive Tregs (ST+ Tregs) and muscle regeneration. Indeed, when they have repeated the same experiment with mice deficient for IL-33 receptor specifically on Tregs, muscle regeneration were impaired [after injury]. Though the authors did not show data whether there was no difference between muscle regeneration between young and old mice when both were deficient for IL-33 receptor specifically on Tregs. Without such data it is not possible to conclude whether difference in IL-33 responsiveness in Tregs accounts for difference between young and old mice with respect to muscle regeneration.
Analysis of IL-33 producing cell within muscle tissue showed that fibro/adipogenic progenitor (FAP) cells were the main producer of muscle IL-33 and they produced less of IL-33 after muscle injury in old mice.
Finally, injection of IL-33 into old mice muscle improved its regenerative potential after injury (however, the authors did not repeat the same experiment with Treg-specific IL-33 receptor deficient mice to formally confirm that beneficial effect of exogenous IL-33 was indeed mediated via Tregs).
In summary, this study suggests that IL-33 improves muscle regeneration, in general. Whether reduced number of IL-33 responsive Tregs in old mice represents only variable between young or old mice with respect of muscle regeneration is not clear from this paper. Basically, In my opinion, the results do not support the paper's conclusions with respect to Tregs.