Peer Review History

Original SubmissionApril 9, 2020
Decision Letter - Ana Fernandez-Sesma, Editor, Stacey Schultz-Cherry, Editor

Dear A/Prof Kedzierska,

Thank you very much for submitting your manuscript "HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells" 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. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

The reviewer's were enthusiastic about the manuscript and the significance of the studies to the field. They had minor comments for consideration.

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Thank you again for your submission to our journal. 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,

Stacey Schultz-Cherry

Guest Editor

PLOS Pathogens

Ana Fernandez-Sesma

Section Editor

PLOS Pathogens

Kasturi Haldar

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0001-5065-158X

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

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The reviewer's were enthusiastic about the manuscript and the significance of the studies to the field. They had minor comments for consideration.

Reviewer Comments (if any, and for reference):

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 work, the authors studied the immunodominance status of influenza-specific universal CD8+ T-cells in HLA-I heterozygote individuals, which express two or more universal HLAs for Influenza A. The article brings interesting data showing that, while CD8+ T-cell responses directed towards A2/M158 are generally immunodominant, this response is markedly diminished in individuals expressing also the HLA-B*27:05. The authors show that A2+B27- individuals present highly functional TRBV19/TRAV27 TCRab clonotypes, but that in B27+ persons, A2 cells present increased diversity and increased prevalence of private less functional clonotypes, explaining partially the differential immunodominance of responses. The immunodominance of B27 restricted T-cells has been already demonstrated over the B8 ones (Boon et al., 2002), and, in experimental mice models, the co-expression of B7 and B27 alleles is associated with a B7 immunodominant responses (Akram and Inman, 2013). Although the immunodominance in the context of influenza infection has been already demonstrated in several studies, this article is interesting in showing that HLA-B27 alters the immunodominance hierarchy and functional properties of universal influenza-specific CD8+ T cells, impacting the response of the most prevalent HLA across multiple ethnicities. The understanding of immunodominance in the context of Influenza infection is crucial for the development of T-cells based therapy. The manuscript is clear and well written. The present group has a recognize expertise and many high-quality publications in the field of CD8+ T cell responses in Influenza infection. I have only minor comments.

Reviewer #2: This is a very well-written manuscript investigating CD8 T cell immunodominance in HLA heterozygotes. The authors have found that A2/M1 CD8 T-cells in non-HLA-B*27:05 individuals were immunodominant, contained public TCR clonotypes and displayed highly polyfunctional and proliferative capacity. However, in HLA-B*27:05-expressing donors, A2/M1CD8 T-cells were subdominant, with distinct TCR clonotypes and diminished avidity, proliferation and polyfunctionality. This study will not only help us understand the protective CD8 T cell responses following influenza infection in different individuals, but also have significant impact on the future design of CD8 T cell-based influenza vaccines. The reviewer only has one minor comment regarding the manuscript: if the information is available to the authors, please list age, sex and ethnicity information of the blood donors in a table during revision.

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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: None

Reviewer #2: N/A

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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: • In keywords: correct the word “immunodominance”;

• In abstract, replace the full stop after “capacity” with a comma;

• In results, correct the text for Figure 2C (line 204). It’s indicating Figure 5C;

• About the data Figure 6 and related text , is it correct to conclude that B27 cells are more proliferative than A2 cells based on the numbers of tetramer+ cells and IFN-gamma production upon stimulation??

• Can the authors discuss the fact that A2 and B27 cells (i) present different phenotypes, (ii) althodo not differ in terms of cytotoxins expression?

Reviewer #2: If the information is available to the authors, please list age, sex and ethnicity information of the blood donors in a table during revision.

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Reviewer #1: No

Reviewer #2: No

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Revision 1

Attachments
Attachment
Submitted filename: Response_to_reviewers PLoS Path.docx
Decision Letter - Ana Fernandez-Sesma, Editor, Stacey Schultz-Cherry, Editor

Dear A/Prof Kedzierska,

We are pleased to inform you that your manuscript 'HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells' 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.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens.

Best regards,

Stacey Schultz-Cherry

Guest Editor

PLOS Pathogens

Ana Fernandez-Sesma

Section Editor

PLOS Pathogens

Kasturi Haldar

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0001-5065-158X

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

***********************************************************

Reviewer Comments (if any, and for reference):

Formally Accepted
Acceptance Letter - Ana Fernandez-Sesma, Editor, Stacey Schultz-Cherry, Editor

Dear A/Prof Kedzierska,

We are delighted to inform you that your manuscript, "HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells," 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

orcid.org/0000-0002-7699-2064

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