Dear Dr. Wu,

Thank you very much for submitting your manuscript "A Computational Study of Co-inhibitory Immune Complex Assembly at the Interface between T cells and Antigen Presenting Cells" for consideration at PLOS Computational Biology.

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,

Guanghong Wei

Associate Editor

PLOS Computational Biology

Nir Ben-Tal

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: In the paper "A Computational Study of Co-inhibitory Immune Complex Assembly at

the Interface between T cells and Antigen Presenting Cells", Su et al develop a coarse-grained mesoscale model of protein-ligand and protein-protein interactions in order to elucidate their mechanisms of assembly in T cells.

The main novelty of the approach relies in accounting for different binding interfaces and kinetic rates, which give rise to different steady state properties of the system. The author carry on a systematic parameter scan in order to evaluate the relative importance on these parameters on the amount and relative types of interactions.

While the paper is interesting and the result are novel I recommend three minor modifications:

1) a more systematic and quantitative comparison of the obtained results with experiments. This comparison is often implied, but a quantitative description would strengthen the conclusions.

2) A careful editing of the paper. A number of sentences would benefit from a grammar check.

3) A few general sentences in the introduction about the mechanisms of T cells assembly at interface would better familiarize the reader with the specific topic of the paper.

Reviewer #2: The manuscript by Su et al. reports a coarse-grained reaction-diffusion simulation model of T cell receptors, CTLA-4 and PD-1, and their corresponding antigen presenting cell (APC) ligands, B7 and PD-L1. By varying the binding constants in the model, the authors showed that cis-interactions between the two ligands on the APC membrane can inhibit CTlA-4/B7 oligomerization because of the competition for an overlapped B7 binding and homodimerization site. The introduction of PD-1 into the system reduces the inhibition by competing for the PD-L1 binding site that is shared with B7. The authors suggest these competitive bindings can regulate the signalling pathways activated by B7 and PD-L1.

To be acceptable for publication, the authors should address the following issues:

1. The simulation model assumes that a dimer of CTLA-4 can bind to two B7 monomers simultaneously. Reference to previously reported structural or other experimental evidence that support this assumption should be provided.

2. The translational diffusion coefficient of the ligand-receptor complex was set to 5 um2/s but for ligand-ligand hetero- and homo-dimers, the coefficient is 0 um2/s. Why the discrepancy? Would letting all dimers, whether they are ligand-receptor or ligand-ligand, diffuse at 5 um2/s change any of the results presented in the manuscript?

3. In the model, the ratio of CTLA-4 to B7 is always fixed to 1:1, which is likely not the case in vivo. The authors should show how does the correlation between CTLA-4/B7 trans-interaction and B7 homodimerization in Figure 3 change when the ratio is changed.

There were some language issues, for example:

page 6: "Incorporate these factors into.."

page 15: "-3kT, even the number..."

page 17: "In another word,..."

page 28: Caption of Figure 4: "In addition to CTLA-4 and B7, ligand PD-L1, we further introduced PD-L1 into the simulation system."

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: None

Reviewer #2: No: Ideally, the software and simulation model should be made accessible to reproduce the results.

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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 in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you deposit 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. For instructions, please see http://journals.plos.org/compbiol/s/submission-guidelines#loc-materials-and-methods

Dear Dr. Wu,

We are pleased to inform you that your manuscript 'A Computational Study of Co-inhibitory Immune Complex Assembly at the Interface between T cells and Antigen Presenting Cells' has been provisionally accepted for publication in PLOS Computational Biology.

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 Computational Biology. 

Best regards,

Guanghong Wei

Associate Editor

PLOS Computational Biology

Nir Ben-Tal

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have successfully addressed all my concerns and I recommend publication

Reviewer #2: The authors have revised the paper according to reviewers' comments. They have clarified points raised and performed new simulations reported in new graphs and referenced more relevant literature. The response of the authors to all the previous recommendations is satisfactory. I am happy to recommend the paper for publication as it is.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: None

Reviewer #2: No: I could not find numerical data that underlies graphs in a public repository or in spreadsheet form as supporting information.

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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