Immunology

Evaluation Summary:

This submission represents a holistic approach to how pentraxin 3 (PTX3) modulates susceptibility to experimental infection by Streptococcus pneumoniae. The authors have built robust findings on the importance of PTX3 for the survival of mice and they have extensively investigated all different aspects of the mechanism of PTX3 protection. One main strength of the manuscript is its usage of bone marrow chimeras in addition to total as well as tissue-specific mouse strains that support their claims.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors show that a widely used knock-out mouse for Mertk carries multiple additional changes in its genome, affecting the expression of a number of genes besides Mertk. They show that, although the line was back-crossed to the C57 background, these changes are due to the original 129P2 genome of the embryonic stem cells in which the knock-out was originally created. Through the generation of two new knock-out mouse strains, in C57 embryonic stem cells, the authors here show only part of the phenotype of the original Mertk knock-out mouse can be reproduced. Overall, this study raises awareness as to the limitations of the Mertk-/- v1 model and limits direct inference of Mertk-/-v1 observed phenotypes to Mertk deficiency alone.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This report identified NK-extracellular-vesicle (NK-EV)-associated microRNAs and characterized them by small RNA next-generation sequencing. They found that NK-EVs promote Th1 polarization and activation of monocyte and monocyte-derived dendritic cells. The findings are potentially important for understanding NK cell function.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors set out to investigate the roles of SMAD4 and TGFbeta in regulating memory CD8 T cell differentiation during viral infection. To achieve their goal, the authors utilized a variety of available tools including, gene expression, mice that lack certain regulatory genes, and different tissue tissue culture approaches. Although the in vitro experiments yielded interesting results that will interest students of T cell immunology/biology, there is an absence of results from in vivo studies that would validate the in vitro observations.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Patients with Gaucher disease can have significant and crippling neurological manifestations. The study uses novel mouse models of neurodegeneration associated with glucocerebrosidase 1 (GBA1) deficiency. It provides a detailed analysis of the alterations caused by targeted deletion of GBA1, including cellular, genetic and metabolic alterations in neurons, microglia, and infiltrating immune cells. The work defines novel mechanisms driving neuroinflammation in neuronopathic Gaucher disease.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This study describes a new antibody to identify human neutrophil extracellular traps (NETs) also in tissue samples. The paper might not only introduce an important novel tool for many areas of biomedical research, but it also touches cell biological questions of importance. The usefulness of the NET-specific antibody is impressively developed in the paper, while the mechanistic concepts are not yet fully established.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The manuscript by Luo et al. showed that the cytokine receptor DR3 is selectively expressed on thymic NKT17 cells and DR3 ligation leads to the activation of NKT17 cells in the thymus. Overall, The presented experiment are properly executed, controlled and presented. The finding that DR3 acts as a costimulatory molecule for thymic NKT17 cells is interesting. The mechanism and the functional relevance of this finding remain wanting.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript reports a new approach to the important and challenging problem of predicting T cell receptor:peptide-MHC interactions, one that relies on molecular model building (with previously published tools) followed by feature extraction and machine learning. The strengths of the study are more conceptual than practical: the overall framework and analytical approach; a balanced, critical assessment of the method's performance (which does not shy away from negative results); some observations on TCR:pMHC docking geometry. On the practical side, the classifier does not appear to generalize well to unseen epitopes (neither do the published tools it's compared to), so at the end of the day it's not clear that it will be preferable to simpler sequence-based approaches.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript analyses the inhibitory role of IL-10 producing regulatory T-cells in a mouse cytomegalovirus infection model. The authors report that IL-10 producing CD4+T-cells express genes of chronically activated Th1-cells, are clonally expanded and inhibit anti-viral T-cell responses via arginase, an enzyme that breaks down an essential amino acid for T-cell activation. The manuscript presents some novel and potentially important data; however, it requires the provision of additional experimental data and clarifications.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript described a role of Vitamin C in promoting plasma cell differentiation by remodeling the epigenome via TET (Ten Eleven Translation) family proteins. Overall, most of experiments are properly executed, controlled and presented. This paper will be of interest to scientists in molecular immunologists, particularly those involved in of epigenetic mechanisms of B cell differentiation to plasma cells.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)