Immunology and Inflammation

eLife assessment

This paper seeks to understand how the presentation of peptides by medullary thymic epithelial cells may be regulated by the MHCII peptide loading modulator, H2-O, and how this may affect the selection of regulatory T (Treg) cells. Further work is needed to ensure that the findings are robust: currently the analysis of data is inadequate and inconsistencies in the reported findings are not placed in context with results from other groups. The current version does not provide sufficient support for the claims regarding the effects on Treg cell selection.

eLife assessment

The authors aim to elucidate the mechanism by which pyroptosis contributes to the increased release of procoagulant tissue factor-containing microvesicles. The data are intriguing and attempt to shed light on the mechanism by which GSDMD plays a role in releasing tissue factor-containing microvesicles, albeit incomplete. The manuscript offers valuable information to unveil new therapeutic targets in human diseases such as sepsis, which can be further strengthened by consulting the reviewers' suggestions.

eLife assessment

This study examines the expression of HDAC3 within DC compartment. Taking advantage of tamoxifen inducible ERT2-cre mouse model they observe the dependency of pDCs but not cDCs on HDAC3. The requirement of this histone modifier appears to occur during development around the CLP stage. Tamoxifen treated mice lack almost all pDC besides lymphoid progenitors. RNA seq studies identify multiple DC specific target genes within the remaining pDC - using Cut and Tag technology they validate some of the identified targets of HDAC3. Taken together, this study shows the requirement of HDAC3 on pDC but not cDC, congruent with the recent findings of a lymphoid origin of pDC.

eLife assessment

This study provides useful insights into the subcellular localization, interaction with integrins, and functional importance of the cell surface receptor Piezo1 in migrating human T-cells. Whether Piezo1 is critically sensing mechano-physical cues during T-cell migration is however not well supported by direct experimental evidence. The data collected is solid otherwise.

eLife assessment

This important study by Lu et al aimed to determine the key factors of T cell responses associated with durable antibody responses following the initial two shots of COVID-19 mRNA vaccinations. By comparing the SARS-CoV-2 spike protein (S)-specific T cell subsets between "Ab sustainers" and "Ab decliners" that were present post-vaccination, the authors concluded that S-specific CD4+ T cells in "Ab sustainers" were enriched with Tfh cells. There is solid evidence as the authors applied multiple methods and approaches to address the key questions, and the presented data are robust.

eLife assessment

This study presents valuable data on the antigenic properties of neuraminidase proteins of human A/H3N2 influenza viruses sampled between 2009 and 2017. The antigenic properties are found to be generally concordant with genetic groups. Compared to a previous version, additional analyses have strengthened the work, with solid evidence supporting the claims of the authors.

eLife assessment

The authors' findings have theoretical or practical deep implications, which makes them important. The methods, data, and analyzes support the authors' arguments with only minor weaknesses, and overall they are solid. In vitro culture experiments could provide evidence to strengthen the evidence for the functional significance of Th1-mediated cytokines in the observed B cell responses.

eLife assessment

The important work by Aballay et al. significantly advances our understanding of how G protein-coupled receptors (GPCRs) regulate immunity and pathogen avoidance. The authors provide convincing evidence for the GPCR NPR-15 to mediate immunity by altering the activity of several key transcription factors. This work will be of broad interest to immunologists.

eLife assessment

This is an important and interesting account of the ability of Ym1 crystals to promote type 2 immunity in vivo, in mice. The data presented are compelling, building on and significantly advancing evidence this group has previously published on the type 2 immunogenicity of other protein crystals. The work will be of relevant interest to immunologists and researchers working on type 2 inflammatory disease, in the lung and in others tissues.

eLife assessment

This study illuminates the effects of ultrasound-induced extracellular vesicle interactions with macrophages. It provides solid data offering insights that will be potentially useful in exploring therapeutic approaches to inflammation modulation, by suggesting that ultrasound-treated myotube vesicles can suppress macrophage inflammatory responses.

eLife assessment

This valuable study evaluates the effects of nifuroxazide on radiotherapy for the treatment of hepatocellular carcinoma. Solid evidence is provided to support the conclusion that nifuroxazide facilitates the downregulation of PD-L1 and may improve therapy outcomes when combined with radiotherapy, though the inclusion of additional cell lines and animal models would have strengthened the study. This work will be of interest to cancer biologists and those working in immuno-oncology.

eLife assessment

Studying several allergens in different mouse strains, the authors assess the role of IgM in airway inflammatory responses and show that IgM deficient mice have reduced airway hyperresponsiveness. Although the findings, based on experimental evidence from a wide range of immunological and other assays, including the expression of a protein that regulates actin in smooth cells, are interesting and useful, the study is incomplete as the data and analyses do not support their primary claims.

eLife assessment

Despite the importance of long-lived plasma cells (LLPCs), particularly in the vaccination field, their natures are still unclear. In this valuable manuscript, as a first step towards clarifying these natures, the authors used a solid genetic approach (time-stamping one) and successfully labelled only functional LLPCs. Although four groups have already published data by the same genetic approach, the authors' manuscript includes additional significant findings in the LLPC field.

eLife assessment

This manuscript presents a valuable approach to exploring CD4+ T-cell response in mice across stimuli and tissues through the analysis of their T-cell receptor repertoires. The authors use a transgenic mouse model with reduced diversity of the T-cell receptor repertoire to elicit more consistent T-cell responses across individuals, demonstrating challenge-specific and tissue-specific responses of regulatory T-cells. The evidence for the authors' conclusions is solid, and the work will be of interest to immunologists studying T cell responses.

eLife assessment

This study provides valuable new insights as to how two evolutionary conserved motifs in CD4 contribute to the CD4-mediated enhancement of TCR signaling independently of the CD4-LCK interaction. The data at hand are convincing, even if confined to a cell line model and not substantiated in vivo and with little new mechanistic insight provided regarding the domains of CD4 shown to have significant roles in the signaling process. Without the data from primary cells it is difficult to make statements about the quantitative contribution of LCK-dependent and independent functions of CD4 in TCR signaling.

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.