Research Briefing in 2025

T cell exhaustion is a major barrier to antitumor immunity and limits the success of immunotherapies. We show that binding of thrombospondin-1 (TSP-1) to CD47 on CD8⁺ T cells promotes exhaustion through a calcineurin–NFAT–TOX signaling pathway. Disrupting this interaction prevents T cell dysfunction and enhances the efficacy of immunotherapy.

Systemic hypoxia is sufficient to induce persistent neutrophil dysfunction in humans, months after acute respiratory distress syndrome or high-altitude conditions. This dysfunction is mediated by loss of the histone modification H3K4me3. In hypoxic mouse models, we show that this reduction in H3K4me3 originates in neutrophil progenitor populations and is a consequence of histone 3 clipping.

Because they are a main source of the antiviral cytokines type I and III interferons, plasmacytoid dendritic cells are considered to be essential for host defense against viral infections. Contrary to this dogma, we show that they are dispensable or even detrimental in mice.

Rapidly progressive glomerulonephritis refers to a group of severe autoimmune kidney diseases. Using high-resolution spatial transcriptomics, we identified a common pathway of disease progression and uncovered sequential PDGF and TGFβ activation of parietal epithelial cells as critical drivers of glomerulonephritis. Our study provides valuable insights that could result in disease stage-specific treatment options.

Our study defines and spatially maps skin fibroblasts in both health and disease. We categorize fibroblast subtypes based on their association with scarring risk across 23 skin diseases and perform cross-tissue comparisons to identify shared fibroblast states.

The artificial intelligence (AI)-designed peptide SK56 blocks mature gasdermin D pores, delaying pyroptosis and inflammatory cytokine release. This reduces dendritic cell hyperactivation and prevents the spread of pyroptosis to nearby cells. SK56 also protects against mitochondrial damage and improves survival in septic mice, demonstrating its potential as a new post-pyroptosis, anti-inflammatory therapy.

We identified T cell receptors (TCRs) targeting antigenic peptides that contain a shared β-catenin mutation (CTNNB1^S37F) presented on common human leukocyte antigen alleles. TCR-engineered T cells eliminated patient-derived tumors and prevented relapse in vivo in mice, highlighting a strategy to exploit public neoantigens for TCR-based immunotherapy in solid cancers.

Cholesterol-dependent cytolysins produced by diverse bacterial pathogens are internalized by host cells and translocate to the trans-Golgi network (TGN). They remodel the TGN into a platform for assembly of the NLRP3 inflammasome, a crucial innate immune signaling pathway in host defense and pro-inflammatory diseases.

Using in vivo CRISPR–Cas9 screens of CD8⁺ T cells in a melanoma model, we identified STUB1 as an inhibitor of T cell-mediated antitumor immunity. STUB1 forms a complex with CHIC2, and together, they negatively regulate the expression of cytokine receptors, thereby limiting intratumoral CD8⁺ T cell numbers and function.

Adoptive T cell therapies show limited efficacy against solid tumors owing to T cell exhaustion within the tumor microenvironment. A study now reveals that dysregulated translation, rather than transcriptional changes alone, drives T cell dysfunction by creating mitochondrial imbalance through selective protein synthesis.

When dendritic cells migrate through narrow gaps, they transiently assemble a mechanosensitive actin structure in front of their nucleus. This structure pushes outward against the surrounding tissue to help widen a path so the bulky cell body can pass through. At the same time, it acts as a mechanical ‘capacitor’ that helps the cell to balance forward protrusion at the leading edge and outward protrusion at the cell body.

Single-cell spatial proteomics paired with chromatin accessibility mapping identifies a diverse range of human microglial immune states. In Alzheimer’s disease, hippocampal microglia tend to lose antigen-presenting function and become disengaged from inhibitory synapses. Our dual-modality approach illustrates the importance of integrating local tissue architecture and cell identity to fully understand disease-associated immune remodeling.

Using genetic modifications to dissect mitochondrial functions, we found that, on acute stimulation, CD8⁺ T cells require mitochondrial metabolism to sustain proliferation and prevent exhaustion. Mitochondria-derived reactive oxygen species are also needed to generate memory CD8⁺ T cells.

Effector CD4⁺ T cells restore antiviral CD8⁺ T cell function in the liver by licensing Kupffer cells via CD40–CD40L interactions. This triggers IL-27 production and reprograms the hepatic immune environment. This liver-intrinsic pathway of T cell help is relevant for chronic hepatitis B virus infection and may apply to other conditions with persistent antigen stimulation, such as cancer.

We show that mutations in the CSF1R gene, which cause the rare neurodegenerative disease ALSP, lead to the loss and abnormal activation of microglia. This triggers glial stress and the emergence of disease-associated oligodendrocytes with impaired myelinating potential. These findings suggest potential therapeutic strategies by modulating glial stress pathways or enhancing compensatory microglial support mechanisms.

We identify a clonally expanded subset of granzyme K-expressing CD8⁺ T cells that establish residency in the central nervous system, where they target microglia and help to control the spread of pathogenic phosphorylated tau (pTau) — a hallmark of Alzheimer's disease and other tauopathies. This CD8⁺ T cell subset is also found in human brains with pTau lesions.

We show that deletion of PD-1 enhances regulatory T (T_reg) cell immunosuppressive function in the tumor microenvironment. This increased T_reg cell function results from upregulation of a co-inhibitory receptor network driven by CD30 on PD-1-deficient T_reg cells. Blocking CD30 reverses T_reg cell-mediated promotion of tumor growth.

We investigated how previous immunity and intrinsic immunogenicity affect the generation of immune responses to SARS-CoV-2 variants. Although previous immunity partially reduces subtype-specific responses to a new virus variant, we found that poor immunogenicity of the mutated epitopes in the infecting virus has a larger effect on limiting new responses.

Using spatial single-cell transcriptomics of human lung biopsies, we mapped cellular interactions at the airway wall in health and asthma. We identified specialized cellular communities marked by high levels of chemokine and alarmin expression. These cellular hubs likely have a crucial role in immune cell training and become dysregulated in asthma.

Using a fate-mapping autoimmune arthritis mouse model and single-cell RNA sequencing, we identified aberrant T follicular helper (T_FH) cells that arise owing to T cell plasticity in the gut and are highly pathogenic. Importantly, the mucosal gene signature of T_FH cells also exists in patients with rheumatoid arthritis.