Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Vallejo-Bermudez et al. summarize and discuss a wide range of findings and concepts on CD57 in T lymphocytes including CD4+, CD8+ and other subsets, as well as in NK cells. This review article covers historic to recent key findings on CD57, similarities and differences among cell types, potential controversies and current consensus, roles of CMV and other chronic infections, and clinical relevance to vaccination and non-infectious diseases as well (such as cardiovascular diseases, autoimmune diseases, and cancer). The figure and tables are helpful and informative. This reviewer has the following minor suggestions and comments:

• Clinical Implications and Therapeutic Perspectives: This section reads well, as other sections do. At a first glance, this reviewer misunderstood that there might be some strategy directly targeting CD57 itself or CD57-expressing cells, which currently seems impractical. A clarifying sentence or two would help avoid potential misunderstanding.

Editorial improvement and corrections are recommended. For example:

• TEMRA should be spelled out and briefly explained at its first appearance. Possibly other abbreviations too, if not common to non-expert readers.
• Lines 105-106 need corrections.
• Excessive line breaks in the lower part of page 5.

Author Response

We thank the reviewer for the constructive comments and suggestions that helped us improve the manuscript.

Comment 1: Clinical Implications and Therapeutic Perspectives: This section reads well, as other sections do. At a first glance, this reviewer misunderstood that there might be some strategy directly targeting CD57 itself or CD57-expressing cells, which currently seems impractical. A clarifying sentence or two would help avoid potential misunderstanding.

Response 1: We thank the reviewer for this helpful observation. We agree that CD57 is currently best interpreted as a differentiation and immune-history marker rather than a practical direct therapeutic target. To avoid potential misunderstanding, we have added a clarifying sentence in the Clinical Implications and Therapeutic Perspectives section explicitly stating that CD57 itself is not currently a feasible direct therapeutic target and that clinical strategies should focus on upstream drivers (e.g., chronic antigenic stimulation and CMV-associated immune remodeling) rather than on CD57-expressing cells per se.

Comment 2:Editorial improvement and corrections are recommended. For example:

TEMRA should be spelled out and briefly explained at its first appearance. Possibly other abbreviations too, if not common to non-expert readers.

Lines 105-106 need corrections.

Excessive line breaks in the lower part of page 5.

Response 2: We thank the reviewer for these helpful editorial suggestions. We have carefully revised the manuscript to improve clarity and formatting. Specifically:

(i) TEMRA and other potentially non-obvious abbreviations are now spelled out and briefly defined at first mention; (ii) lines 105–106 have been corrected for language and syntax; (iii) excessive line breaks have been removed and the formatting has been standardized. Additional minor editorial corrections have also been implemented throughout the text to improve readability.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive and well structured overview of the biology, differentiation, and clinical relevance of CD57expressing lymphocytes, integrating a substantial body of relevant literature. In my opinion,however a more detailed description of the methodological background would be warranted. At present, it is not entirely clear whether the selection of sources was performed using a systematic or a narrative approach, which databases and search strategies were applied , or whether any quality assessment of the included studies was carried out. A brief clarification of these aspects would substantially improve the transparency and methodological rigor of the review.

The discussion of the concepts of “senescence” “exhaustion” “terminal differentiation” and “immunological "age, represents a valuable part of the manuscript. Nevertheless, a more structured presentation of the definitions and their distinctions., -possibly in the form of a table or schematic figure, would greatly assist readers in interpreting the terminology accurately.

The statement referring to CMV as a dominant driver appears somewhat strongly formulated in its current form. It would be advisable to present more explicitly the evidence supporting this claim in comparison with other contributing factors, such as age, metabolic status, or chronic inflammation, preferably citing quantitative or meta-analytical data where available, and emphasizing the multifactorial nature of the process.

Overall , the manuscript is a valuable and informative contribution and I consider it suitable for publication after minor clarifications and revisions.

Author Response

We thank the reviewer for the careful evaluation of our manuscript and for the constructive and helpful comments and suggestions.

Comment 1: This manuscript provides a comprehensive and well structured overview of the biology, differentiation, and clinical relevance of CD57expressing lymphocytes, integrating a substantial body of relevant literature. In my opinion, however a more detailed description of the methodological background would be warranted. At present, it is not entirely clear whether the selection of sources was performed using a systematic or a narrative approach, which databases and search strategies were applied , or whether any quality assessment of the included studies was carried out. A brief clarification of these aspects would substantially improve the transparency and methodological rigor of the review.

Response 1: We thank the reviewer for this constructive suggestion. This article was designed as a narrative (non-systematic) review rather than a formal systematic review or meta-analysis. To improve transparency and methodological clarity, we have now added a dedicated paragraph in the Introduction describing the literature search approach, including databases consulted, general search terms, selection criteria, and the absence of formal study-quality scoring. We believe this clarification strengthens the methodological transparency while remaining consistent with the narrative review format.

Comment 2: The discussion of the concepts of “senescence” “exhaustion” “terminal differentiation” and “immunological "age, represents a valuable part of the manuscript. Nevertheless, a more structured presentation of the definitions and their distinctions., -possibly in the form of a table or schematic figure, would greatly assist readers in interpreting the terminology accurately.

Response 2: We thank the reviewer for this helpful suggestion. We agree that clearer conceptual structuring improves interpretability. To address this point, we have added a new summary table that explicitly contrasts the concepts of cellular senescence, T-cell exhaustion, terminal differentiation, and immunological age, including defining features, functional characteristics, typical markers, and biological context. This table is now referenced in the section discussing CD57 and differentiation states to guide readers in the correct interpretation of terminology.

Comment 3: The statement referring to CMV as a dominant driver appears somewhat strongly formulated in its current form. It would be advisable to present more explicitly the evidence supporting this claim in comparison with other contributing factors, such as age, metabolic status, or chronic inflammation, preferably citing quantitative or meta-analytical data where available, and emphasizing the multifactorial nature of the process.

Response 3: We thank the reviewer for this important comment. We agree that the role of CMV should be framed within a multifactorial context. We have therefore moderated the wording in the relevant sections and now present CD57⁺ and CD28null lymphocyte expansion as the result of combined influences including chronic viral exposure, age, and host and inflammatory factors. We have added explicit comparative statements and supporting references to better contextualize the relative contribution of CMV versus other drivers and to emphasize interindividual and subset-dependent variability. We believe these changes improve balance and clarity while remaining consistent with the available quantitative evidence.