https://orcid.org/0000-0003-0380-1527
Peer Review History
| Original SubmissionOctober 8, 2021 |
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Dear A/Prof Kedzierska, Thank you very much for submitting your manuscript "HLA-A*11:01-restricted CD8+ T cell immunity against influenza A and influenza B viruses in Indigenous and non-Indigenous people" for consideration at PLOS Pathogens. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments. We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation. When you are ready to resubmit, please upload the following: [1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. [2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file). Important additional instructions are given below your reviewer comments. Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts. Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments. Sincerely, Christian Munz Associate Editor PLOS Pathogens Sonja Best Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************** Reviewer's Responses to Questions Part I - Summary Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship. Reviewer #1: In this manuscript, Habel et al. aim at characterizing HLA-A*11:01-restricted CD8+ T cell responses in HLA-A*11:01-expressing Indigenous and non-Indigenous Australian donors. To this end, the authors used an experimental approach, which combined mass spectrometry analysis to identify peptides expressed by HLA-A*11:01 and in vitro T cell stimulation for testing their immunogenicity. Although the results of this analysis may help increase our knowledge of the CD8+ T cell response against Influenza viruses, data provided in the study are limited (especially for IAV reactivity) and do not allow to make general conclusion on immunodominant epitopes involved in potentially protective CD8+ immune response in HLA-A*11:01+ individuals. Overall, developing a universal influenza vaccine based on this evidence would be quite ambitious. Reviewer #2: This is an interesting and well-performed study of HLA-A*11:01-restricted CD8+ T cell responses to influenza A and B virus peptides. HLA-A*11:01 is an allele prevalent in East Asia and Oceania, and highly expressed in indigenous populations at high risk of influenza infection. Current influenza vaccines are designed primarily to induce neutralizing antibodies against hemagglutinin and neuraminidase. Improving the efficacy of influenza A and B vaccines may be achieved by targeting and activating influenza-specific cytotoxic CD8+ T cells and memory formation. The authors used Masspec to identify influenza A- or B-derived peptides eluted from HLA class I after infection of APCs in vitro. 79 influenza A and 57 influenza B derived peptides were subsequently screened for immunogenicity in HLA-A*11:01-positive PBMC assays. The authors identified three immunodominant influenza A- and three influenza B-derived peptides from PB1, PB2, M, NS1 and NP proteins that appeared highly conserved among influenza viruses. The study also includes data on structures of HLA-A*11:01 in complex with influenza B-derived peptides identified. Since this lies outside of my field of expertise, I will not comment on this part of the study. This study's results may inform the design of future influenza vaccines more suitable to meet the needs of indigenous populations, but also the design of more effective influenza vaccines in general, by focusing on viral proteins distinct from hemagglutinin or neuraminidase, targeted by CD8+ T cells. ********** Part II – Major Issues: Key Experiments Required for Acceptance Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions. Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject". Reviewer #1: Given the variability in the T cell responses and the low number of donors analyzed, this reviewer believes that including more donors in the screenings shown in Fig. 2 and 4 may help for a better definition of statistical significance in immunodominant epitopes presented on HLA-A*11:01 and targeted by CD8+ T cells in HLA-A*11:01+ donors. Conclusions regarding immunodominance are made on very few donors (e.g. 2 out of 4 donors, Fig. 2A; 1 out of 3 donors, Fig. 2B etc.), thus resulting limited and potentially biased due to the low number of donors tested. Reviewer #2: Main points: C1R cells express endogenous HLA-C*04:01, so eluted peptides may bind to this allele rather than the transduced HLA-A*11:01. The data is corrected by subtracting peptides identified in previous studies using similar technology. This limitation is clearly mentioned in the manuscript already. Another limitation concerns the low number of PBMC samples stimulated with a given peptide in screening experiments testing PBMC peptide reactivity, derived from 3 individuals per peptide only. This may have reduced the number of peptides identified, and could also have introduced false positive results, particularly since all 4 indigenous donors were also positive for HLA-A*02:01. Identified peptides were tested with more PBMC samples in the experiment shown in figure 7, but also there the possibility that responses to the identified “HLA-A*11:01” peptides were actually caused by presentation on HLA-A*02:01 is not excluded. This issue could be addressed by stimulating donor PBMCs with the identified peptides presented by C1R cells transduced either with HLA-A*11:01 or -A*02:01. Also regarding the low number of PBMC samples stimulated with any given peptide, how did the authors define immunodominance for the purpose of this manuscript? ********** Part III – Minor Issues: Editorial and Data Presentation Modifications Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. Reviewer #1: Plots result often difficult to interpret: 1) Which donors have been used in each experiment in Fig. 2, 4, 5 and 7? In order to help readers interpret the plots, each donor should be shown with a different symbol and the donor code should be indicated in the legend. Did you use the same or different donors for the screenings showed in Fig. 2, 4, 5 and 7? 2) In Fig 5 different symbols are used to distinguish between Indigenous and non-indigenous donors. This reviewer wonders whether this info is really relevant for the interpretation of the results. 3) How did the authors set the cut off of positive or negative response? The results are shown as % IFN-γ+ of CD8+ T cells, but what was the range of basal IFN-γ expression? Showing the “No Ag” condition as well as providing a description of the rationale for determining positivity would be helpful. 4) Information about the antibody staining panels and gating strategy used to identify epitope-reacting CD8+ T cells is not provided in the text. This information should be added in the method section. Did you gate on CD8+ IFN-γ+ cells or only on IFN-γ+ total population? How did you define activated CD8+ T cells when showing the combination of cytokine expression (CD107a, IFN-γ, MIP1-b, TNF)? 5) When possible, statistical analysis should be applied and shown in the plots (e.g. Fig 5). Reviewer #2: No comments ********** PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Figure Files: While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Data Requirements: Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here on PLOS Biology: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5. Reproducibility: To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. 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| Revision 1 |
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Dear A/Prof Kedzierska, We are pleased to inform you that your manuscript 'HLA-A*11:01-restricted CD8+ T cell immunity against influenza A and influenza B viruses in Indigenous and non-Indigenous people' has been provisionally accepted for publication in PLOS Pathogens. Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests. Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated. IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript. Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS. Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Christian Munz Associate Editor PLOS Pathogens Sonja Best Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************************************************** The authors have significantly improved the manuscript by increasing the number of HLA-A*1101+ tested individuals to 24 (identified after HLA typing of more than 300 donors). They confirm their identified HLA-A*1101 binding peptides and immunogenicity of these. Furthermore, they have now performed more stringent statistical analysis for positive T cell responses and visualized individual donors by separate symbols in the figures. The presented study contributes to our understanding of influenza specific cellular immunity in Asian populations. Reviewer Comments (if any, and for reference): |
| Formally Accepted |
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Dear A/Prof Kedzierska, We are delighted to inform you that your manuscript, "HLA-A*11:01-restricted CD8+ T cell immunity against influenza A and influenza B viruses in Indigenous and non-Indigenous people," has been formally accepted for publication in PLOS Pathogens. We have now passed your article onto the PLOS Production Department who will complete the rest of the pre-publication process. All authors will receive a confirmation email upon publication. The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Pearls, Reviews, Opinions, etc...) are generated on a different schedule and may not be made available as quickly. Soon after your final files are uploaded, the early version of your manuscript, if you opted to have an early version of your article, will be published online. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers. Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens |
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