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Major Issues

1. Limited mechanistic characterization of antiviral immunity While Treg depletion improves viral clearance, the study does not clearly define which immune cell populations (e.g., CD8⁺ T cells, CD4⁺ T cells, or innate immune cells) are primarily responsible for this effect. Functional analyses such as cytokine production or cytotoxic activity would strengthen the conclusions.

2. Lack of transcriptional profiling of Tregs and Tconvs The study focuses on cell frequency and activation markers but does not include comprehensive gene expression analyses (e.g., RNA-seq or scRNA-seq). This limits understanding of whether neonatal Tregs represent a functionally distinct population.

3. Absence of epigenetic analysis Given the emphasis on early-life immune programming, it is unclear whether the observed tolerogenic states are associated with stable epigenetic modifications such as histone acetylation or DNA methylation. This represents a key missing layer in the mechanistic framework.

4. Incomplete characterization of microbiota-driven effects Although microbial exposure is shown to increase Treg abundance, the study does not identify specific microbial taxa or metabolites responsible for this effect. Analysis of microbiome composition and metabolite profiling would provide deeper insight.

5. Limited exploration of metabolic dysfunction mechanisms The study reports metabolic abnormalities following neonatal Treg depletion but does not investigate the underlying pathways (e.g., adipose inflammation, insulin resistance, or hepatic metabolism). This weakens the interpretation of long-term outcomes.

Minor Issues

1. Terminology consistency Terms such as “tolerance,” “suppression,” and “tolerization” are used interchangeably and could benefit from clearer definitions.

2. Integration of findings across tissues While multiple organs are discussed, the connections between them are not fully integrated into a unified model.

3. Discussion depth The discussion could be strengthened by addressing how metabolic and epigenetic mechanisms may contribute to the observed phenomena.

Competing interests

The author declares that they have no competing interests.

Use of Artificial Intelligence (AI)

The author declares that they used generative AI to come up with new ideas for their review.