PONE-D-21-22116PD-L1 IS EXPRESSED ON HUMAN ACTIVATED NAIVE EFFECTOR CD4+ T CELLS. REGULATION BY DENDRITIC CELLS AND REGULATORY CD4+ T CELLSPLOS ONE

Dear Dr. Mazerolles,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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5. Review Comments to the Author

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Reviewer #1: In the this study the authors present their observation that PD-L1 is expressed in activated human CD4+ T cells. They assess correlation expression levels of PD-L1 and other positive and negative costimulatory receptors such as ICOS, PD-1, CTLA4, TIGIT in T effector and Treg cells during culture of naïve CD4+ T cells with SEE superantigen and dendritic cells.

They found that activated T effector cells expressed BTLA, ICOS, PD-1 and PD-L1, whereas Treg cells expressed TIGIT, ICOS and CD27. They also observed that expression of PD-L1 in T effector cells positively correlated with their proliferation during exposure to SEE in the presence of DC. Titration experiments of Treg addition in the culture showed that suppression of T effector cell activation by the addition of Treg resulted in diminished expression of PD-L1. Based on these findings, the authors proposed that PD-L1 expression on T effector cells might serve as a marker of their activation and might be a useful biomarker in conditions of aberrant T cell activation such as in autoimmune diseases.

The results are interesting but not surprising based on our knowledge about the expression of these surface receptors in T cell subsets, including T effector cells and Treg.

Specific points:

1) Several previous studies have shown that PD-L1 is expressed in activated T cells (e.g. Bardhan et al. Sci Rep 2019; 9: 17252; Diskin et al. Nat Immunology 2020; 21: 442). Thus, this observation is not made for the first time as stated by the authors.

2) The authors correlated the expression of PD-L1 with the proliferation state of T effector cells. It is important to examine cytokine production by T cells under the same conditions.

3) The studies as they stand are only correlative and the role of PD-L1 in regulating the function of T effector and Treg cells has not been examined. This aspect should be addressed by using appropriate antibodies targeting each of these surface receptors.

4) All the experiments have been performed using SEE. It is well established that superantigens overcome the standard signals medicated by TCR and accessory molecules, including co-inhibitory and co-stimulatory receptors. For this reason, it would be more appropriate to assess the proposed role of these surface molecules of their interest in an antigen-specific system.

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Reviewer #1: No

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PD-L1 IS EXPRESSED ON HUMAN ACTIVATED NAIVE EFFECTOR CD4+ T CELLS. REGULATION BY DENDRITIC CELLS AND REGULATORY CD4+ T CELLS

PONE-D-21-22116R1

Dear Dr. Mazerolles,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Prof. Pierre Bobé

Academic Editor

PLOS ONE