Immunology and Inflammation

eLife assessment

Toll like receptor 2 (TLR2) signaling has traditionally been viewed a surface protein that induces innate immune responses and improves acquired immunity. Here, the authors suggest a different role for TLR2 in the hair cycle. By using a Cre reporter that is largely, but not solely active in hair follicle stem cells, the authors conditionally delete Tlr2 in mice and report that BMP signaling is sustained and hair cycle entry is delayed. Delving further, the authors identify CEP (2-ω-carboxyethyl pyrrole) as an endogenous ligand of TLR2 in hair follicle stem cell regulation. Although a role for TLR2 signaling in hair follicle stem cells is potentially novel and important, the reviewers remain in consensus that evidence presented in two significant areas continues to be incomplete: 1) where TLR2 and CEP are expressed and how specific is their expression to the hair follicle stem cells; 2) whether as the authors suggest, TLR2 functions by regulating BMP signaling in the stem cell niche of the hair follicle.

eLife assessment

This useful study proposes a role of lysosomal Ca2+ release in inflammasome signaling and metabolic inflammation. While the proposed model would be of considerable interest to the field of immunology if validated, the experimental approaches to study calcium dynamics are problematic, with one of several concerns being the transfection efficiency. The major claims of the paper are thus only incompletely supported.

eLife assessment

This is an important study that investigates the role of commensal microbes and molecules in the antigen presentation pathway affecting the development and phenotype of an unusual population of T lymphocytes. The authors provide compelling evidence to identify a population of unconventional T cells that exist in the small intestinal epithelium, which appear to depend on commensal microbes, and show that a single commensal microbe (that encodes an antigen capable of weakly stimulating these cells) is sufficient to maintain this T cell population.

eLife assessment

The present study shows that the expression of some inhibitory receptors (IRGs) on CD8 T cells is increased in people living with HIV (PLWH) and remain elevated even after years of viral suppression by antiretroviral therapy. The authors further report that inhibition of TGIT partially restores the ability of CD8 T cells to produce CD107a but not the other functions. Altogether, the results provide some valuable insights into our understanding of inhibitory receptor expression in the HIV infected individuals but some evidence seems incomplete.

eLife assessment

This useful study tests the hypothesis that Mycobacterium tuberculosis infection increases glycolysis in monocytes, which alters their capacity to migrate to lymph nodes as monocyte-derived dendritic cells. The authors conclude that infected monocytes are metabolically pre-conditioned to differentiate, with reduced expression of Hif1a and a glycolytically exhaustive phenotype, resulting in low migratory and immunologic potential. However, the evidence is incomplete as the use of live and dead mycobacteria still limits the ability to draw firm conclusions. The study will be of interest to microbiologists and infectious disease scientists.

eLife assessment

The study has added value to what we have already known in the potential pharmacological immunomodulatory therapies in LPS-induced sepsis, and especially the use of oral leucine might be of great interest to the readers engaged in this field. We believe this study is important and provides solid evidence on the potential use of leucine in sepsis.

eLife assessment

This study presents a useful description of transcriptional responses in adult zebrafish olfactory bulb microglia and neurons following exposure to infectious hematopoietic necrosis virus. This solid work advances our understanding of central nervous system responses to viral infection and provides an inventory of gene expression changes in particular cell types that can be used as hypothesis generators for future studies. Experiments to assess behavioral and neural responses to the virus in adults and larvae are inadequate and would benefit from a clearer conceptual framework that connects these avenues of investigation both to published literature and to the authors' single cell RNA sequencing results.

eLife assessment

In this valuable contribution, the authors demonstrate that the infusion of NAD+ may prevent death and reduce disease severity from lethal experimental bacterial sepsis, possibly through inflammasome inhibition, without reducing bacterial load. They provide solid evidence for these protective effects of NAD+, though the precise mechanisms involved remain unclear and need further support and elucidation. The core findings may well have clinical implications but, in addition to mechanistic clarifications, contextualised interpretation as metabolic adaptation to sepsis would create wider interest.

eLife assessment

This manuscript describes a unique humanized model of MS/EAE-like pathology and provides a valuable new model that incorporates enhanced susceptibility related to HLA type. The data are modestly incomplete to solid in terms of supporting their claims that this model improves upon prior models. Overall, these claims could be further supported by a more comprehensive quantification of the immune infiltrate, a better assessment of peptide sensitization requirement, and an assessment of CNS/spinal cord pathology.

eLife assessment

Host cell death is an effective strategy to protect against infection, and is believed to function primarily by the elimination of the intracellular niche for pathogen replication. Abele and colleagues address an important question: does the mode of cell death affect its effectiveness in pathogen clearance? Consistent with prior observations, the authors provide compelling new evidence that the answer can depend on the cell type and/or tissue involved.

eLife assessment

This study addresses how protein synthesis in activated lymphocytes keeps up with their rapid division, with important findings that are of significance to cell biologists and immunologists endeavouring to understand the 'economy' of the immune system. The work is supported by solid data. Because it proposes non-conventional mechanisms, the study sets the scene for further work in this area.

eLife assessment

Yamamoto and Matano provide solid evidence that a G63E/R CD8+ T-cell escape mutation in the accessory viral protein Nef may facilitate the induction of neutralizing antibody (nAb) responses in rhesus macaques infected with SIVmac239. Functional analyses support that this mutation specifically impairs Nef`s ability to stimulate PI3K/Akt/mTORC2 signalling. This important study suggests that the accessory viral Nef protein impairs B cell function and effective humoral immune responses and is of interest for researchers and physicians interested in HIV/AIDS and vaccine development.

eLife assessment

Using state-of-the-art fate-mapping models and genetic and pharmacological targeting approaches, this study provides important findings on the distinct functions exerted by resident and recruited macrophages during cardiac healing after myocardial ischemia. Evidence supporting the conclusions are solid with the use of the FIRE mouse model in combination with fate-mapping to target fetal-derived macrophages. This study will be of interest for the macrophage biologists working in the heart but also in others tissues in the context of inflammation.

eLife assessment

This valuable study presents findings on the mode of action of MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c), and its impact on monocyte-derived macrophages. The authors present solid evidence for its increased expression in stimulated monocytes/macrophages, its direct bactericidal functions, as well as its role in the modulation of monocyte differentiation into macrophages. Since most of the data were generated from a cell line (THP1), future work is required to validate observations in primary cells and to further support the claims of this work.

eLife assessment

This is an important study that revealed a new noncoding RNA regulatory circuit involved in T cell function. The authors provide compelling evidence, that is more rigorous than the state-of-the-art, using genetically engineered mice and cell-based experiments. The interpretation of the results should be tempered due to the small effect size observed.

eLife assessment

This study presents the valuable finding that sustained calcium signaling in induced-Treg (iTreg) cells can lead to the loss of Foxp3 expression and iTreg identity by altering the chromatin landscape. The evidence supporting the claims of the authors is convincing. The work will be of interest to immunologists working on Treg cell therapy.

eLife assessment

This important work advances our understanding of the import of clonal heterogeneity in cancers in immune response to individual antigens. The evidence supporting the conclusions is convincing, and uses interesting tools, although the mechanistic basis of the observations is unclear. The work will be of broad interest to immunologists including cancer immunologists.

eLife assessment

The authors generate a new formulation built upon a previous nanoparticle platform to generate a new system termed bicontinuous nanospheres (BCN), allowing for the dual incorporation of lipid and protein antigens. The authors generate mycolic acid (MA)-loaded BCN and perform a series of characterization studies to demonstrate the superior performance of this new formulation relative to the original one in terms of antigen persistence, a quality needed to sustain responses after vaccination. This work provides important new insights relevant to the TB vaccine field and it suggests that alternative antigens to proteins could be used in TB vaccine formulations. The data are convincing and will be of interest to individuals working on tuberculosis, vaccines and basic immunology.

eLife assessment

This manuscript provides important findings and would be of interest to specialists and researchers dealing with polycystic ovarian syndrome. Based on the compelling evidence, the authors present significant results on the role of B cells in immune cell activation in PCOS. However, there are some remarks regarding the statistics and data presentation.

eLife assessment

This important work advances our understanding of TLR7 signaling at epithelial surfaces that drives monocytes expansion and its impact on viral responses. The evidence supporting this conclusion is solid, particularly data demonstrating TLR7 stimulation and the requirement for TLR7 in the monocyte expansion. The work will be of interest to immunologists and virologists.