Immunology

eLife assessment

This paper will be of interest to the audience in the fields of genome stability and B lymphocyte biology for highlighting the role of R loop metabolism in maintaining genome integrity during antigen gene diversification. Although RNA:DNA hybrids and R loops have been described at the immunoglobulin (Ig) loci long ago, their contribution to Ig heavy chain (Igh) class switch recombination and Igh locus integrity have not been fully elucidated yet. Overall, the experiments and results generally support this conclusion; however, several aspects of the model put forward are highly speculative in the current form.

eLife assessment

This paper addresses an important question within adaptive immunity, namely whether the T cell receptor (TCR) repertoire of negatively selected thymocytes shares common features. The authors analyze T cell receptor sequences from mice as they progress through positive selection, CD4/CD8 lineage commitment, and negative selection, to find small but consistent differences between the repertoires at these selection stages. They argue that their findings do not indicate any sequence-specific selection; however, some of the conclusions drawn are currently incompletely supported by the performed analyses.

eLife assessment

This is a very elegant study which clearly demonstrates the existence of CMV specific memory T cells in CMV+ pre-pandemic individuals that are capable of recognising epitopes from SARS-CoV-2. It provides new insights into the development of cross-reactive immune cells that was not anticipated. The study has been elegantly performed and presents important findings. In particular, the discovery of a public TCR which mediates the crossreactivity described is an important finding.

eLife assessment

This fundamental study demonstrates that the two isoforms of the ARPC5 subunit (ARPC5 and ARPC5L) of the Arp2/3 complex have specific functions in regulating cytoplasmic and nuclear actin filament assembly in response to DNA replication stress and T cell receptor signaling in T lymphocytes. The data presented in the manuscript are convincing and of good technical quality, and the study provides interesting new insights into specific cellular roles of different Arp2/3 isoforms in T lymphocytes.

Evaluation Summary:

The manuscript by Kane et al. described transcriptional profiles of various subsets of activated iNKT cells using longitudinal scRNA-Seq analysis. The finding that IL-10 producing iNKT cells have a cMAF-associated gene signature similar to Tr1 cells is novel. Overall, the data is well presented, however, functional consequences of some findings require further investigation.

(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:

The authors dissect the phenotypes of bone-marrow derived myeloid cells in a murine model of pulmonary vasculitis with relevance to human disease, revealing the association of novel phenotypic subsets associated with lung injury, yet the role of these subsets in regulating or contributing to tissue injury is less clearly determined.

(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 reviewer remained anonymous to the authors.)

Evaluation Summary:

This manuscript addresses a long-standing question regarding the highly variable cellular composition and functions as well as immune environments along the epididymis. Using multiple mouse models (bacterial infection and parabiosis between WT and Ccr2 KO) in conjunction with powerful scRNA-seq analyses, the authors provided solid evidence supporting the notion that resident immune cells are strategically positioned along the epididymal duct, potentially providing different immunological environments required for sperm maturations and elimination of pathogens ascending the urogenital tract.

(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:

The authors investigate how HIV-1 infection affects the immune response in the context of SARS-CoV-2 infection by characterising the circulating B cell response. They conclude that people with HIV-1 infection, who become infected by SARS-CoV-2, produce B cell responses via an extra-follicular pathway to a greater degree than people who do not have HIV-1 infection. These findings imply that in HIV-1 infected individuals, long-term B cell and antibody responses against SARS-CoV-2 might not be as robust and durable compared to those in people without HIV-1 infection. The manuscript will be of interest to infectious disease specialists, virologists, and immunologists.

(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:

In this manuscript entitled "Dietary palmitic acid induces innate immune memory via ceramide production that enhances severity of acute septic shock and clearance of infection" Seufert and colleagues have investigated how saturated fatty acids increase susceptibility of the host in a murine model of LPS-mediated septic shock. Pretreatment of macrophages with palmitic acid (PA) was found to reprogram macrophages towards hyper-inflammatory phenotype, which was dependent on ceremide. Importantly, depletion of macrophages intracellular ceremide with oleic acid reversed their hyper-inflammatory phenotype. Interestingly, while PA was harmful in the LPS-acute septic shock model, it was beneficial in clearance of C. albicans in Rag-deficient mice lacking both B and T cells. While this is an exciting study, the presented data don't fully support the central hypothesis and the link with trained immunity is currently weak.

(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.)

eLife assessment

This paper reports on important observations regarding human CD8 T cells that express shared T cell receptors amongst individuals and exhibit poly-specificity directed mainly to several unrelated viral antigens. Although the majority of the claims are convincingly supported by results from both in silico and experimental approaches, mechanistic molecular details underlying poly-specificity remain incomplete. The results from these studies will enhance the ongoing debate on T cell specificity and potentially, will impact fields related to immunology, for example, immunoparasitology, cell biology, and vaccine development.