Issues

Rapid production of the effector cytokine IFN-γ by natural killer (NK) cells is critical for host defense against viral infection. In activated NK cells, IL-12 remodels the RNA polymerase II landscape within minutes, increasing IFN-γ promoter occupancy and pausing in a STAT4- and DDX5-dependent manner.

Depending on the immunization route, location, and antigen dose, BACH2 exerts bidirectional regulation on the differentiation of CXCR5⁻ versus CXCR5⁺ CD4⁺ T cells, orchestrating systemic immunity throughout the body.

Lin et al. identify eIF3e as a translational checkpoint that maintains immune tolerance. Deleting eIF3e in B cells drives pathological B–T cell interactions, lymphoproliferative disease, and lymphoma, highlighting translational control as a critical mechanism protecting against immune dysregulation and cancer.

Harms Pritchard et al. dissect key CD4⁺ T cell/B cell interactions to define signals that govern the development of MBC populations. Surprisingly, IgM⁺ MBCs that form secondary plasmablasts require many of the key programs as IgG⁺ MBCs but do not require GC T follicular helper cells to achieve this state of differentiation.

Yan et al. show that basal skull bridging vein–associated ACE structures enable CSF flow from the SAS into the dura, whereas spinal meninges lack these gateways, defining compartmentalized clearance regulated by anatomical exit zones and parenchymal border macrophages.

Gruber et al. identify STAT2 mutations in a family with severe early-onset pulmonary alveolar proteinosis (PAP), a rare lung disease marked by alveolar surfactant accumulation. By demonstrating that the excessive type I interferon inflammation driven by these STAT2 variants impairs monocyte chemotaxis, this study uncovers a novel mechanism of PAP.

This study identifies a new mechanism driving kidney fibrosis. Researchers reveal that IFN-λ, produced by renal tubular epithelial cells, directly activates renal fibroblasts to cause fibrogenesis. Blocking IFN-λ signaling can delay progression of renal fibrosis.

The study by Ongaro et al. identifies IRF8 as a tumor-specific regulator driving CD8⁺ T cell exhaustion: induced by TCR but suppressed by chronic IFN-I, IRF8 promotes TOX and represses effector functions; targeting IRF8/IRF-family network restores anti-tumor immunity, informing immunotherapy strategies for cancer therapy.

Alcaraz-Serna et al. have engineered regulatory T cells to specifically target the major birch pollen allergen Bet v1. These cells suppressed allergic immune responses and reduced airway inflammation in mice, opening novel strategic avenues for treating allergic asthma.

We report four rare or common hypomorphic IL23R variants that, when present in the homozygous state, impair IFN-γ production by innate-like T and NK cells, thereby conferring a predisposition to tuberculosis.

Due to alternative splicing that removes the transmembrane domain–encoding exon, CD137 exists in both soluble and membrane forms. This study indicates that both forms of CD137 expressed by Foxp3⁺ CD4 T cells are critical for immunoregulation, and they independently restrain T1D development.

The nervous system is increasingly recognized as a regulator of cancer progression. Chang et al. describe how peripheral neurons shape solid tumors through interactions with cancer, immune, vascular, and stromal cells and highlight the therapeutic potential of targeting neural pathways to improve treatment response.

Type III IFNs, or IFNλ, are pleiotropic immune mediators that mostly work at mucosal surfaces by signaling in epithelial cells and selected immune cells. Zhou, Zhang, and colleagues demonstrate that IFNλ also signals in kidney fibroblasts sustaining renal fibrosis.

B–T cell cross talk is safeguarded by central and peripheral tolerance and cell-intrinsic checkpoints. In this issue of JEM, Lin et al. show that altered translation in early germinal center B cells triggers a vicious cycle of aberrant B–T cell interactions culminating in lymphomagenesis.

In this issue of JEM, Schroeder et al. report that the transcription factor BACH2 has context-dependent dual functions in regulating the differentiation of follicular T helper cells.