Research Briefing

Homeostatic immune cells remain perpetually vigilant against pathogens. We found that baseline JAK–STAT signaling supports the characteristic transcriptional and epigenetic state of homeostatic T cells and macrophages in mice. JAK–STAT signaling under homeostatic conditions was driven by signals from healthy tissue and did not require external immune stimuli.

We report two patients with biallelic SHARPIN deficiency, which manifests with autoinflammation and B cell immunodeficiency and is phenotypically distinct from Sharpin deficiency in mice. In one patient, there was a significant shift from pro-survival signaling to cell-death signaling in fibroblasts and lymphoblasts induced by members of the TNF cytokine superfamily, accounting for the autoinflammation and immunodeficiency. Targeted therapy with TNF inhibitors had a dramatic beneficial effect.

The transient expression of CD61 and its unconventional pairing with CD103 at the immune synapse enhances T cell receptor signaling, improves anti-tumor cytotoxicity and mitigates tumor growth. Clinically, CD61⁺ tumor infiltrating lymphocytes (TILs) exhibit enhanced effector functions and show limited cellular exhaustion.

The intestinal immune response is tightly controlled to limit inflammation, largely by the cytokine IL-10, which prevents colitis. We report that the transcription factors c-MAF and BLIMP-1 induced IL-10 in T cells in the colon, but also acted to negatively regulate distinct cytokine pathways to restrict pathobiont-induced colitis.

In this study, we use a transcriptomic approach as a starting point to explore the heterogeneity of human GATA3-expressing lymphocytes across different tissues and disease contexts. We identify, characterize and functionally validate an abundant progenitor-like memory T cell population with the potential to sustain pathogenic T_H2 cell inflammation.

Autoantibodies that develop in systemic lupus erythematosus (SLE) can cause long-term cognitive impairment that remains even after the systemic disease becomes quiescent. This study attributes the persistent cognitive symptoms of SLE to a self-sustaining neuroinflammatory process that continues indefinitely unless disrupted — which can be done using medications approved by the US Food and Drug Administration.

Bacillus Calmette–Guérin (BCG) is the only available vaccine against tuberculosis. As well as being an effective vaccine against tuberculosis, BCG also provides off-target protection against various pathogens. Here, we report a mechanism for BCG-mediated cross-protection against influenza A virus (IAV), which requires a dialogue between the innate and adaptive immune memory systems.

In this study, we developed an adenoviral-vectored vaccine that targets the spike protein of BA.5 Omicron SARS-CoV-2. When nasally delivered in mice and hamsters, the vaccine stimulated mucosal antibody production and CD8⁺ T cell responses, and demonstrated protection against several SARS-CoV-2 strains, including the antigenically distant Omicron XBB.1.5 strain. Immune cell depletion studies showed that cross-reactive memory CD8⁺ T cells contribute to the cross-protection that is conferred by nasal vaccines against respiratory infection with antigenically shifted SARS-CoV-2 Omicron strains.

Cancer cells often rely on glycolysis for energy metabolism. Increased glycolysis leads to the increased production of lactate and H⁺ ions, which should hypothetically lower intracellular pH. However, we find that tumor cells combat intracellular over-acidification by synthesizing carnosine, especially under hypoxic conditions, which allows them to control lysosome-dependent galectin-9 expression and evade T cell-mediated immune surveillance.

In this proof-of-concept study, we present a next-generation poxvirus vaccine that features a ‘two-in-one’ immunogen. Our protein vaccine construct, DAM, combines the monkeypox virus antigens A35 and M1, and was produced on the basis of structure-guided design. The DAM subunit vaccine elicited superior antiviral immunity with safety compared to cocktail vaccines or a live vaccinia virus vaccine.

Sepsis is a global health issue in great need of effective therapies. Analysis of gene expression profiles in different tissues and at the whole-body level in mice enabled the characterization of the organism-wide host response to sepsis, which will help to build a unified mechanistic framework for the disease.

The effectiveness of pneumococcal vaccines declines with age for unknown reasons. We studied the responses of older adults to the 23-valent PPSV23 and the 13-valent PCV13, identifying distinct baseline immune characteristics associated with vaccine responsiveness, including a cytotoxicity signature associated with weaker responses to PCV13.

The alarmin IL-33 activates type 1 and type 2 immune cells via its receptor ST2 in a context-specific manner. We discovered a type 1 immunity-restricted promoter of the ST2-coding gene Il1rl1, which is located far upstream of the curated gene and is crucial for antiviral CD8⁺ cytotoxic T cell and CD4⁺ T_H1 cell responses.

We describe a system for introducing guide RNAs (gRNAs) to Cas9-expressing hematopoietic stem cells, which are used to generate mice with gene knockouts in the immune system. By using different gRNA-containing vectors and Cas9-expressing mice, we created systems for knockout of single genes or pairs of genes constitutively or inducibly.

Mouse macrophages express specialized genes particular to the organs they inhabit, but whether the same applies in humans is unclear. In human peritoneal fluid, we identified many macrophage phenotypes, including two specialized macrophage types that corresponded to distinct mouse peritoneal macrophages. However, their abundances were markedly different between species.

Interleukin-27 (IL-27) is a pleiotropic cytokine known for its diverse immune regulatory properties. Although innate immune cells are considered the major cellular sources of IL-27, we found that gut regulatory T cells (T_reg cells) secrete IL-27 under inflammatory conditions, allowing them to selectively limit intestinal helper T17 cell (T_H17 cell) responses in various disease settings.

Cancer cells often overexpress CD47, which triggers the macrophage receptor SIRPα to elude anti-tumor immunity. We found that CD47 also suppresses phagocytosis by masking a pro-phagocytic ligand, SLAMF7, on tumor cells. We generated a first-in-class SLAMF7 antibody, which dissociated the CD47–SLAMF7 cis interaction, enabling anti-tumor immunity during SIRPα blockade.

After acute injury to skeletal muscle, an ‘early responder’ subtype of stromal cells rapidly produces an array of inflammatory mediators. Disruption of this response causes abnormal accumulation of several adaptive lymphocyte populations, a prolongation of inflammation, and an effect on tissue regeneration.

A trimodal single-cell assay reveals a previously unknown T cell subset and cellular state differences between children and older adults that might contribute to age-specific immunity.

Genetic and environmental diversity are major drivers of macrophage transcriptional responses, but the mechanisms that underlie the relative contributions of gene-by-environment interactions to transcriptional responses of tissue macrophages are unclear. We defined the relative effect of cis regulation, cell-autonomous trans regulation, and non-cell-autonomous trans regulation of Kupffer cell gene expression.