PCOMPBIOL-D-26-00157

The SATvac model of CD8+ T cell expansion and contraction phases considering memory and effector cell differentiation

PLOS Computational Biology

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Stacey D. Finley, Ph.D.

Section Editor

PLOS Computational Biology

Additional Editor Comments (if provided):

Thank you for your patience as we worked through the peer review process. Reviewer 1 has substantial and constructive feedback. These should be thoroughly addressed. We will then consider the revised manuscript.

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1) Please ensure that the CRediT author contributions listed for every co-author are completed accurately and in full.

At this stage, the following Authors/Authors require contributions: David A. Christian, and Thomas A Adams II. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: My comments are uploaded as an attachment.

Reviewer #2: This manuscript describes the SATvac model, a stochastic, agent-based model incorporating CD8+ T cell responses to vaccination, including effector/memory differentiation. The model is grounded in biological assumptions that are supported by prior experimental and modelling literature.

The authors extend their previous STORE model (which focused only on activation at the priming site) to include multiple tissues (draining/non-draining lymph nodes, spleen, omentum and peritoneum), effector/memory differentiation and extending the simulation period to 25 days post vaccination, capturing the contraction phase. The model is fit to experimental data from CPS-OVA vaccination in mice, the same model as used previously. Model fitting to experimental data is performed using particle swarm optimisation (PSO), a global optimisation approach. The authors appear to have done due diligence to ensure the robustness of the fits.

In support of the stochastic nature of lymphocyte proliferation the authors may wish to consider the relevance of the Cyton/Cyton2 models (Hawkins PNAS 2007, Subramanian J Math Biol 2008, Cheon Front Bioinf 2021) and related evidence for independence of division, death, differentiation and isotype switching in B cells (Duffy Science 2012). These studies emphasise the sensitive dependence of stochastic systems to small changes in model parameters, including high variability at the peak of response expected based a branching processes.

In summary, the manuscript is methodologically sound, and I support the first principles approach of model construction based on rules grounded in experimental evidence. In complex in vivo systems the goal is not always to obtain the ‘best’ fit using the simplest possible model as this may lead to over-simplification and misleading conclusions (e.g., that the system is deterministic). Consistency with the in vivo data is a remarkable achievement when paired with orthogonal experimental evidence for the underlying assumptions. This study illustrates the utility of stochastic agent-based models in simulating in vivo immune responses that is broadly applicable across a variety of systems, and may plausibly lead to insights that may allow optimisation of therapeutic strategies such as vaccination, when combined with better understanding of the molecular pathways controlling the stochastic modules.

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes: Mark R. Dowling

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Attachments

Attachment

Submitted filename: Reviews.docx

Dear Prof. Adams II,

We are pleased to inform you that your manuscript 'The SATvac model of CD8+ T cell expansion and contraction phases considering memory and effector cell differentiation' has been provisionally accepted for publication in PLOS Computational Biology.

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

Best regards,

Stacey D. Finley, Ph.D.

Section 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: My previous concerns have been addressed.

Reviewer #2: The authors have addressed my comments and the manuscript is acceptable for publication in my view. Congratulations on on thorough job in balancing biological principles with pragmatic fitting of in vivo experimental data.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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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.

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Reviewer #1: No

Reviewer #2: No