Issues

Fibroblastic reticular cells are the source of Notch ligands promoting the differentiation of short-lived effector CD8⁺ T cells. Induction of early Notch signals in CD8⁺ T cells enhances the opening of chromatin regions occupied by bZIP transcription factors.

This work demonstrates that group 2 KLF family transcription factors are critical for specifying the identity of distinct tissue-resident macrophages. KLF2 directly controls expression of genes previously shown to be necessary in cavity macrophages, while KLF4 may play a similar role in alveolar macrophages.

Mutations in the KRT14 gene cause epidermolysis bullosa simplex (EBS), featuring abnormal basement membrane zone (BMZ) function. We identified deleterious variants in HMCN1 co-segregating with severe EBS and found that HMCN1 directly binds keratin 14 and critically contributes to the BMZ integrity.

This study unveils a novel mechanism by which the metabolic enzyme PCK1 hinders cGAS-STING activation by competitively consuming GTP, consequently fostering tumor immune evasion.

Ise et al. identify integrin β7⁺ plasma cells that migrate from secondary lymphoid tissues to bone marrow, where they persist. Their egress into blood depends on the transcription factor KLF2, which regulates S1pr1 expression.

RNA splicing factor mutations are common in cancer, but connecting phenotypes to specific mis-spliced genes has been challenging. We show that RBM10 loss leads to exon inclusion of transcripts regulating ECM–cytoskeletal interactions and RAC1-GTP activation, sufficient to promote metastatic fitness.

Broomfield et al. demonstrate that early type I interferon blockade alters CXCR3 chemokine regulation and cell location to promote an antigen-dependent CD8⁺ T cell transition of precursor of exhausted T cells to stem cell–like memory CD8⁺ T cells for enhanced protection following viral infection and mRNA–lipid nanoparticle vaccination.

Many PARPs are IFN-stimulated genes, of which PARP7 potently inhibits IFN signaling. Jeltema et al. show that Parp7 deficiency in mice leads to systemic autoimmunity and lung disease that are mediated by IRF3 transcriptional activity.

Homozygous ATRIP splice variants are identified in patients with microcephalic primordial dwarfism and immunodeficiency, highlighting ATRIP’s essential role in the replication stress response, chromosomal stability, and immune cell viability and proliferation, providing insights into the molecular basis of these complex conditions.

Inborn errors of immunity are monogenic disorders causing immune deficiency and/or dysregulation. This review explores the identification of somatic variants as a cause of these syndromes, including the identification of somatic variants and the mechanisms by which they might lead to immunologic disease.

Spaan, Boisson, and Masters review the known primary disorders of the polyubiquitination pathways in humans that lead to autoinflammation and/or immunodeficiency, providing an overview of the molecular pathogenesis of these disorders and their role in inflammation and infection.

Lymphatic vessels in the lungs play important roles in regulating fluid balance, immune responses, and cancer progression. This article reports an intravital microscopy approach for imaging these pulmonary lymphatics. This technique can also reveal cellular dynamics in other understudied tissue structures.

In this issue, Bergson et al. report on variants in HMCN1 that co-segregate with and account for variations in disease severity in individuals suffering from epidermolysis bullosa simplex. Their findings help explain the clinical heterogeneity observed in this rare skin disorder and related conditions.

In this issue of JEM, Krishnamoorthy et al. identify the loss of the splicing factor RBM10 as a driver of metastasis in thyroid cancer through the regulation of RNA splicing. The synthetic lethal interaction between NF-κB and RBM10 loss reveals a potential therapeutic vulnerability.

In this issue of JEM, Cleary et al. present a new intravital imaging technique using a 3D-printed window device that enables lung lymphatics and their participation in immune cell trafficking events to be visualized in action for the first time in mechanically ventilated mice.