CD163+ red pulp macrophages interact with marginal metallophilic macrophages during blood-stage malaria to maintain splenic architecture

Splenic macrophages adapt to malaria through subset-specific remodeling and inter-macrophage communication. Using fate mapping, single-cell transcriptomics, and genetic perturbation, Mauel et al. show that red pulp macrophages (RPMs) and marginal metallophilic macrophages (MMMs) are predominantly yolk sac derived. They identify a CD163high iron-recycling RPM subset that is lost after malaria and find that stress response factor GDF15-dependent signaling supports MMM maintenance.

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Butyrophilin-like 3 and 8 tetramers clamp Vγ4Vδ1 T cell receptors for antigen-independent activation

BTNL3 and BTNL8 are butyrophilin-like receptors that selectively regulate intestinal Vγ4+ T cells, yet the underlying activation mechanism has remained elusive. Dong et al. reveal that BTNL3-BTNL8 for...

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CCR7+ activated dendritic cells are essential for spontaneous and immunotherapy-driven anti-tumor immunity

Dendritic cells (DCs) can acquire distinct functional states. To examine how different DC states orchestrate anti-tumor immunity, Koufaki et al. develop mouse models to label and ablate CCR7+ DCs and find that this activation state is essential for tumor control by uniquely priming tumor-specific cytotoxic T lymphocytes (CTLs), sustaining their function and enabling responses to immunotherapy.

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Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors

Mutations in proteins with roles in lysosomal function, including progranulin, are linked with neurodegenerative diseases. Tejwani, Heffner, et al. demonstrate that lysosomal dysfunction is sufficient to drive epigenetic, transcriptional, and functional remodeling of microglia and macrophages, including in the context of progranulin deficiency. Their findings connect lysosomal function with microglial state.

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Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases

Lysosomal dysfunction is associated with neurodegeneration. Balak et al. examine the cell-specific effects of lysosomal dysfunction in an MPS-IIIA (Sgsh−/−) model and find that microglia are disproportionately affected. Mechanistically, the MITF/TFE transcription factors cooperate with AP-1/ATF, C/EBP, and PU.1 to drive a lysosome-dependent program within microglia that is shared across neurodegeneration models and Alzheimer’s disease.

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Butyrophilin-like 3 and 8 tetramers clamp Vγ4Vδ1 T cell receptors for antigen-independent activation

BTNL3 and BTNL8 are butyrophilin-like receptors that selectively regulate intestinal Vγ4+ T cells, yet the underlying activation mechanism has remained elusive. Dong et al. reveal that BTNL3-BTNL8 forms an antigen-independent tetramer that drives γδ TCR dimerization and activation, providing a structural basis for tissue-specific immune surveillance.

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Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells

Adherent cells mimic the mechanical properties of their surroundings, becoming stiffer in more rigid environments and softer in more compliant ones. Elbanna et al. find that this environmentally induc...

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The liver-secreted protein FGL1 restrains a subset of innate-like B cell responses via the receptor TACI

Negative regulatory ligands have been underexplored for B cells. Su et al. identify fibrinogen-like protein 1 (FGL1) as a new inhibitory ligand for a transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) on a subset of B cells, exploring the biochemistry, function, and potential application of the FGL1/TACI interaction in lupus-like autoimmune disease.

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Bile acids in cancer: From metabolism to immunomodulation

Fang and Schneider review how bile acids connect host metabolism, microbial ecology, and tumor immunity. They present a spatial and cell-type-aware framework for bile acid immunomodulation and discuss therapeutic opportunities to remodel bile acid-immune circuits in cancer.

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TCR origin and specificity to environmental or self-antigens on distinct antigen-presenting cells determine peripheral Treg cell differentiation

Using CRISPR-based TCR editing, Chi et al. systematically compare gut TCRs recognizing dietary, microbial, and self-antigens to define the principles that govern peripheral Treg cell differentiation. They find that TCR identity encodes pTreg cell generation, phenotype, and antigen-presenting cell dependence, establishing TCR specificity as a primary organizer of peripheral immune tolerance.

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Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells

Adherent cells mimic the mechanical properties of their surroundings, becoming stiffer in more rigid environments and softer in more compliant ones. Elbanna et al. find that this environmentally induced stiffening response shapes metastatic site distribution by preferentially sensitizing cancer cells to cytotoxic lymphocytes in stiff contexts, such as the bone.

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Disease-associated microglia adopt stage-specific phenotypes that regulate T cell fate and immunity in glioma

How brain-resident microglia regulate T cell immunity during glioma progression remains unclear. Qian et al. show that disease-associated microglia (DAMs) are not fixed suppressors but instead evolve with tumor stage. DAMs transition from antigen-presenting and checkpoint-regulatory states to T cell-clearing programs, shaping local T cell responses in the brain.

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Purine and pyrimidine-based bacterial cyclic dinucleotides egress the phagosome and activate the innate immune sensor STING

Innate immune recognition of bacteria is thought to center on cell-surface or endosomal pattern recognition receptors such as TLRs. Ragland et al. identify an intraphagosomal cyclic dinucleotide (CDN)-host transporter-STING axis, wherein cytoplasmic STING acts as a common sensor of diverse bacteria, capable of detecting a broad array of CDN species, including pyrimidine-based CDNs.

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The transcription factor BACH1 couples chromatin priming and repression to enable macrophage plasticity and adaptation

Macrophage plasticity and function involve precise regulation of transcriptional programs. Tzerpos et al. find that the transcription factor BACH1 establishes early chromatin accessibility while maintaining transcriptionally repressive states in naive macrophages before activation. This dual activity—termed pioneer repression—regulates macrophage adaptation and inflammatory kinetics in vivo.

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Autophagy maintains high endothelial venule identity and function during inflammation

High endothelial venules (HEVs) facilitate lymphocyte entry into lymph nodes by displaying peripheral node addressin (PNAd), yet how PNAd is regulated remains poorly understood. Jacobs et al. reveal that autophagy preserves HEV identity and function by sustaining PNAd production. Loss of autophagy impairs lymphocyte recruitment, while targeting this pathway dampens inflammation in mouse models of psoriasis.

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Activation of the auricular vagus nerve reflex suppresses airway inflammation

Bioelectronic technologies are being deployed to treat many inflammatory conditions using transcutaneous auricular nerve stimulation. Shibuya et al. employ viral tracing, chemogenetics, and optogenetics to unveil a sensory skin-lung vagal reflex that suppresses allergic airway inflammation. They identify the neuropeptide CGRPβ as a key mediator and provide a rationale for transcutaneous bioelectronic neuromodulation in asthma.

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Philippe Bousso (1971–2026)

In April of this year, our community lost one of its most brilliant and beloved members, Philippe Bousso. With his unique scientific vision, love of technical innovation, and his generous and kind spirit, Philippe touched many of our lives and gave us a tissue-focused understanding of immune cell function that has transformed immunology.

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