Issues

Mirabile–Brightman and Butterfield review the status of cancer vaccination. They focus on tumor-specific antigens, promotion of antitumor immunity, and optimal early stage clinical settings now allowing for improved outcomes for patients.

T cell engagers are antibody-based therapeutics, which can reprogram T cells for antigen-specific elimination of target cells. Learnings from 12 regulatory approvals establish this off-the-shelf modality as safe and effective for cancer therapy with emerging applications for treating autoimmune diseases.

The cribriform plate is a skull region where olfactory nerves link the nasal cavity and brain. Laaker et al. review evidence that this interface also acts as a gateway between the CNS and the peripheral immune system, with relevance to neuropathologies.

Hu et al. identify transcriptional repressor REV-ERB as a critical regulator of colonic RORγt+ Treg differentiation and function through the Bhlhe40-c-Maf axis, highlighting its potential as a target for improving Treg cell function in inflammatory bowel diseases.

Fetal liver macrophages support red blood cell production and pyrenocyte clearance in the developing embryo. Stifter et al. demonstrate that XPR1, a phosphate exporter and regulator, is required for the development and function of fetal liver macrophages.

The study by Kurz et al. elucidates the ontogeny of fibroblastic reticular cells and vascular smooth muscle cells in mouse lymph nodes from proliferating, CCL19-expressing progenitors and highlights the close lineage relationship of the progeny in the perivascular niche.

We identified peptide sequence principles that drive dendritic cell maturation and broaden tumor-reactive T cell clones, even with non-tumor sequences. These peptides must be expressed intracellularly in vivo as single chain containing MHC class I– and II–restricted non-self immunogenic epitopes.

Trms rapidly establish antiviral states in barrier tissues during reinfection, but the mechanisms remain unclear. Hernández-García et al. reveal that Trm recruit plasmacytoid DCs (pDCs), which promote antiviral immunity through type I IFNs (IFN-Is).

Aroca-Crevillén et al. identify a circadian checkpoint in neutrophils, mediated by the CXCL12–CXCR4 axis, that limits tissue injury by inhibiting their intrinsic circadian clock. Genetic and pharmacological activation via CXCR4 eliminates oscillations in diurnal inflammation and reduces vascular and myocardial injury by inhibiting pathogenic behaviors inside vessels, and repositioning neutrophils inside lesions.

This study reveals that host-generated riboflavin breakdown products, including lumichrome and lumiflavin, can bind to the immune protein MR1. Unlike microbial vitamin B precursors, these compounds reduce MR1 surface levels and may naturally dampen MAIT cell immune activation.

The functional dynamics of the Runt-related transcription (RUNX) factors in initiating T-lineage programs remain unclear. Kama et al. show that Notch-mediated reorganization of RUNX complexes and redeployment of RUNX-binding genomic regions are crucial for triggering the T-lineage program.

Li et al. find that in Paneth cells, ERAdP senses c-di-AMP derived from intestinal microbiota, activating DCV biogenesis and AMP secretion to enhance intestinal defense. The ERAdP–NLRP6–ANXA2 axis is impaired in IBD patients, suggesting this axis might be a potential therapeutic target for infection and inflammation.

Pyrin-associated autoinflammatory diseases (PAAD) are due to mutations in the MEFV gene. Bronnec et al. developed SpeckSeq to evaluate the pathogenicity of 228 MEFV variants. SpeckSeq leads to a revised classification of MEFV variants, new diagnoses, and novel insights on pyrin structure–function relationship.

Tet2^ΔMye exacerbates liver fibrosis through stabilizing Ccl2/Ccl8 mRNAs in pMDMs, creating a chemokine-driven inflammatory loop. Targeting this axis with Bindarit and IL-6 blockade synergistically reduces fibrosis associated with Tet2^ΔMye-related myeloid hematopoiesis.

Rhodehouse et al. characterize a nonhuman primate model of natural control of SIV infection in which the immune system blocks new infection events with an efficiency approaching that of antiretroviral therapy.

Panda et al. identify SLC7A8 as a Th2-specific amino acid transporter essential for Th2 proliferation, cytokine production, and type 2 immunity. Slc7a8 deficiency disrupts metabolism, mTOR, and c-Myc signaling, thereby reducing Th2 responses to helminth infection and allergen-induced inflammation.

We show that bridging veins accumulate amyloid in mouse models of Alzheimer’s disease and human Alzheimer’s disease specimens, associated with impaired cerebrospinal fluid efflux. These findings suggest a role for bridging veins in impaired waste clearance in Alzheimer’s disease.

Lettera et al. show that human hematopoiesis across aging is characterized by stable stem cell numbers and reduced erythroid/lymphoid output. Aged HSPCs retain engraftment yet exhibit impaired differentiation, altered chromatin states, inflammatory signatures, DNA damage, and senescence under stress. Proliferative stress in cord blood HSPCs recapitulates these defects, establishing a model for age-associated hematopoietic decline.

Perivenous tunnels surrounding bridging veins terminate at “arachnoid cuff exit” (ACE) points, which enable waste efflux from the brain. Smyth et al. show that amyloid deposits in ACE in Alzheimer’s disease mice and human samples identify a potential new therapeutic target.