The manuscript “Cellular metabolic regulation in the differentiation and function of regulatory T cells” by Ye Chen et al. is a brief overview on the relationship between metabolic pathways and Treg cell function and differentiation. This is a timely relevant topic that is generating an increasing amount of literature. Understanding the metabolically-linked control of Treg cell function and differentiation may indeed enhance the prospects for new therapeutic approaches in many immune-related conditions.
However, two major concerns diminish this reviewer’s enthusiasm for the manuscript:
Response: We greatly appreciate review one for your supportive comments.
Response: We understand reviewer one’s concern and have carefully edited it accordingly. Jacob Colello, an Immunologist and Biologist has carefully edited English grammar.
Response: Reviewer one’s comments are highly constructive. We have re-structured the MS paper and mainly focused on the mTOR related molecules now. Additionally, we also added the IL-2 pathway in Section 3.6 and discussed the autophagy in Section 1.
The authors summarized recent discoveries on the metabolic regulation of Tregs. This is an area under intense study. So I would suggest the authors cite the most recent works. For example, there is a debate about Treg reliance of FAO with a recent paper Raud B, et al, Cell Metabolism 2018. Similarly, AMPK mediated signaling may not significantly contributes to Treg, because AMPK deficient Tregs appear to be normal (Yang K, et al, Nature 2017). The function of PPARg in Tregs and metabolic diseases were explored in recent papers Bapat SP, et al, Nature 2015 and Cipolletta D, et al, Nature 2012. The papers had different conclusions and they should be discussed.
Some editing may help. A few sentences are difficult to understand. For example, line 57-58, 112-115.
The authors summarized recent discoveries on the metabolic regulation of Tregs. This is an area under intense study. So I would suggest the authors cite the most recent works. For example, there is a debate about Treg reliance of FAO with a recent paper Raud B, et al, Cell Metabolism 2018.
Response: We thank reviewer two for your supportive comments and have added the controversial opinion in Section 1 with updated literatures.
Similarly, AMPK mediated signaling may not significantly contributes to Treg, because AMPK deficient Tregs appear to be normal (Yang K, et al, Nature 2017).
Response: Thanks for your important advice, we have discussed this article and other related papers in Section 3.2 in revised MS now.
The function of PPARg in Tregs and metabolic diseases were explored in recent papers Bapat SP, et al, Nature 2015 and Cipolletta D, et al, Nature 2012. The papers had different conclusions and they should be discussed.
Response: This suggestion has been taken and the discussion on these two articles have been added to revised MS now.
Response: A native English speaker with Immunology/Biology background has contributed to grammar edit.
The review "Cellular metabolic regulation in the differentiation and function of regulatory T cells" (Chen Y. et al.) focuses primarily on the recent research that investigate the impact of distinct cellular metabolic pathways on CD4+CD25+Foxp3+ Treg cells development, trafficking, and function. It is emphasized that Treg differentiation depends more on fatty acid oxidation as energy sources, while effector T cells display more glycolytic metabolic demands, as well as that mTOR signaling pathway is a major player in T cell fate determination, owing to its ability to integrate input signals from major intracellular and extracellular cues, such as growth factors, energy status, oxygen, stress, and nutrients. Besides, the evidence linking the mTOR pathway with Treg differentiation, Treg function, Treg expansion and Treg migration have been presented. In addition, the regulatory effects of other elements with high impact on cellular energy metabolism, such as hypoxia-inducible factor (HIF1α), AMP-activated protein kinase, leptin, peroxisome proliferator-activated receptors, and the aryl hydrocarbon receptor on Treg cells generation and function are highlighted.
The data from collected references clearly showed that the development and immunosuppressive functions of CD4+CD25+Foxp3+ Treg cells are under the control of intracellular pathways that regulate the glycolytic and lipid oxidative metabolic programs during T-cell differentiation. The review is interesting and written by experts in the field. Owing to the crucial function of Tregs in maintenance of immune tolerance and prevention of autoimmune and inflammatory diseases it might be of boarder clinical interest. I would recommend accepting it after minor essential revision.
For better understanding of the presented data it would be helpful to add the following:
Line 162 It should be better explained what is presented in Box 1
Response: we highly appreciate reviewer three’s supportive comments.
In section 2. mTOR
Response: These suggestions are crucial and we have added more details of the mTOR signaling in revised MS now.
In Figure 1:
Response: These suggests have been taken and a short description of Figure 1 has been added now. We also modified the typo.
In Figure 2.
Response: We have added some description of Fig 3 (previous Fig 2) and some explanations of Box 1 in the related parts in revised MS now.
In the whole text:
Response: Thanks for your valuable comments, we have updated all the explanations of abbreviation.
In the Review: "Cellular metabolic regulation in the differentiation and function of regulatory T cells" the authors addressed an interesting topic on how differential aspects of Treg biology are regulated by intracellular metabolic processes. The manuscript is full of signaling molecules and other factors that makes it hard to distinguish which of them are important and which of them are rather of minor importance for Treg biology. Moreover, some of the molecules are introduced by their full names some of them not. In general, abbreviations should be introduced when the molecule is mentioned the first time and afterwards used consistently throughout the text. Figure 1 is not very informative. This figure can be replaced by a scheme showing the different effects of mTORC1 and mTORC2 on Treg generation, expansion and migration. Alternatively, a new figure can be added. Then, the reviewer does not understand what is meant by: "...high doses of IL-2 and rapamycin ...activator of mTOR kinase pathway and a specific inhibitor of mTOR kinase (lines 93-95)". Do IL-2 and rapamycin function in a negative feedback loop mechanism? Figure 2 should also include Ahr. In Box 1, the reviewer would recommend to replace "stable states" by "steady states".
In the Review: "Cellular metabolic regulation in the differentiation and function of regulatory T cells" the authors addressed an interesting topic on how differential aspects of Treg biology are regulated by intracellular metabolic processes. The manuscript is full of signaling molecules and other factors that makes it hard to distinguish which of them are important and which of them are rather of minor importance for Treg biology. Moreover, some of the molecules are introduced by their full names some of them not. In general, abbreviations should be introduced when the molecule is mentioned the first time and afterwards used consistently throughout the text.
Response: We really appreciate your precious comments, we have re-structured this review and updated all the explanation of abbreviation.
Figure 1 is not very informative. This figure can be replaced by a scheme showing the different effects of mTORC1 and mTORC2 on Treg generation, expansion and migration. Alternatively, a new figure can be added. Then, the reviewer does not understand what is meant by: "...high doses of IL-2 and rapamycin ...activator of mTOR kinase pathway and a specific inhibitor of mTOR kinase (lines 93-95)". Do IL-2 and rapamycin function in a negative feedback loop mechanism?
Response: Thanks for your comments, we have added one figure to describe the effects of mTORC1 and mTORC2 on Treg generation, expansion and migration. IL-2 is an activator of mTOR and rapamycin inhibits the activity of mTOR, while we still n
