Immunology

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.)

Evaluation Summary:

This is an interesting study, conducted in mice, that demonstrates for the first time the presence of a large population of cytotoxic CD4+ T lymphocytes in infection with Trypanosoma cruzi, a relevant human pathogen. At present, the relevance of these cells in protective immunity engendered by the host remains unclear. Additional experiments are needed to characterize the functionality of these cytotoxic CD4 T cells vis-a-vis the canonical Th1 T cells. This paper can be of interest to scientists interested in immune responses to parasitic infections.

(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 #3 agreed to share their name with the authors.)

Evaluation Summary:

The authors provide evidence suggesting the gene expression profile of a specific subset of dendritic cells define features of specific forms of non-infectious uveitis. This work suggests specific pathways in these cells that may have mechanistic import in inflammatory eye disease. This manuscript is of interested to immunologists studying autoimmunity and ocular immunity. While the paper is largely descriptive, the data it presents should serve as a valuable resource for generating hypotheses about the pathogenesis of ocular autoimmune 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. Reviewer #1 agreed to share their name with the authors.)