The Journal of Experimental Medicine

CD8+ T cell exhaustion represents a major obstacle to effective cancer immunotherapy. While stem-like progenitor exhausted T (TPEX) cells can differentiate into intermediate (Int-TEX) and terminally exhausted (TEX) subsets, the epigenetic regulation of this process is unclear. We identify the RNA methyltransferase Mettl8 as a critical regulator, with expression significantly higher in TPEX than i…

Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system that can cause strokes and seizures. Aggressive CCM growth follows an endothelial cell two-hit mechanism in which enhanced MEKK3-KLF2/4 signaling stimulates PI3K signaling, but how these pathways are linked has been undefined. Here, we use human CCM specimens, two mouse models of CCM disease, and primary hu…

Fibroblasts play critical roles in regulating cellular relationships during tissue homeostasis, immunity, and tumor biology at multiple sites. However, tools to perturb fibroblasts at just one site in vivo are limited, restricting our understanding of how these cellular relationships act locally. We optimized local gene editing of fibroblasts in mouse tumor models to investigate how fibroblast pe…

Vertebrates rely on a network of blood vessels to meet organ demands for oxygen and nutrients. While endothelial cells are known to transport excess nutrients to white adipose tissue (WAT) for energy storage, how their metabolic state impacts this process remains unclear. Here, we identify MYCT1 as a conserved, pan-endothelial protein essential for WAT expansion. Endothelial-specific MYCT1 deleti…

MYCT1-IFITM2/3 interaction links endothelial endolysosomal trafficking to white adipose tissue expansion and exposes the endothelium as a decisive regulator of systemic energy partitioning, not a passive conduit for nutrient delivery (Wetterwald et al., 2026, https://doi.org/10.1084/jem.20251497).

Humans are disomic. At birth, all nucleated cells in the body have the same genetic material, composed of 22 pairs of autosomes and a pair of sex chromosomes. Half the chromosomes are maternal, and half are paternal. It is thought that the two copies of autosomal genes are equally transcribed and translated in a given cell. This notion, based on Mendelian genetics, has guided the identification o…

The authors regret that, during figure preparation, several incorrect panels were placed in Fig. 5 and Fig. S2.In Fig. 5 C, the first two images partially overlapped (3 mpi WT and SynKO retrosplenial cortex images).In Fig. S2, the WT ADPHF entorhinal cortex image in panel A contained a partial overlap with the WT control sonication entorhinal cortex image in panel D, and the entorhinal cortex ima…

Ly6Chigh monocytes, previously recognized as a pro-inflammatory subset, play critical roles in secondary neuroinflammation in the stroke brain. Growing evidence reveals increased infiltration of myeloid cells with substantial heterogeneity, raising the question of how Ly6Chigh monocyte-derived macrophages in the stroke brain adapt to the ischemic environment. Here, by combining analysis of stroke…

Myeloid cells are present in neoplastic tissues from the earliest stages of transformation through to fully developed tumors. However, their intrinsic dynamism and plasticity make them difficult to target therapeutically. Emerging technologies are uncovering previously unrecognized cellular states and functions, thus reshaping our understanding of myeloid cell biology beyond their traditional inf…

COPA syndrome is a rare monogenic autoinflammatory disease due to heterozygous mutations in COPA, encoding the coatomer subunit α. COPA syndrome demonstrates phenotypic overlap with STING-associated vasculopathy with onset in infancy (SAVI), the latter due to gain-of-function mutations in STING1. Indeed, STING activation is a key driver of the pathogenesis of COPA syndrome, and a recent report su…

NIK (Map3k14) is a central regulator of noncanonical NF-κB signaling and immune homeostasis. Mutations in this kinase are linked to autoimmune disorders, including multiple sclerosis (MS). Both germline and T cell-specific deletion of NIK had been demonstrated previously to be associated with resistance to developing experimental autoimmune encephalomyelitis (EAE), an animal model for MS. In this…

Monocytes populate tissues when local niches are depleted of tissue-resident macrophages, yet the tissue-derived signals controlling monocyte-to-macrophage differentiation are largely undefined. Here, we discovered that the oxysterol receptor GPR183 positions monocytes to sense niche signals that induce lung macrophage differentiation. We found that interstitial macrophages that continuously turn…

Mapping the causal circuits that shape the phenotypic and functional landscape of immune cells remains a formidable challenge. Recent advances in pooled CRISPR-based screens, coupled with multiplexed single-cell profiling and imaging-based spatial readouts, make this goal increasingly attainable. In this Perspective, we discuss how CRISPR-based genetic screens will fundamentally transform our und…

Macrophage antibacterial activity requires mtROS production. The specific gene(s) that participates in the mtROS-mediated antibacterial process remains unclear. We showed that Listeria and Salmonella infections in human and mouse macrophages increased mtDNA copy number with which dictates antibacterial activity. Interestingly, adenylate kinase 4 (Ak4) expression was upregulated in macrophages aft…

The brain encodes and stores information about peripheral inflammation and can directly recapitulate prior inflammatory responses. However, whether individual cytokines activate specific neural circuits to produce distinct physiological responses remains unknown. To address this fundamental question, we mapped brain-wide responses to IL-1β and found prominent engagement of the bed nucleus of the …

Cancer immunotherapy has mostly relied on conventional T cells to achieve success in a limited set of tumor types. A promising avenue to expand the repertoire of cancers effectively treated through immune intervention is to mobilize other anti-tumor effectors, such as γδ T cells. Among these, the Vδ1+ subset commonly predominates within peripheral tissues and within tumors, typically associating …

Innate immune cells can retain molecular imprints of past encounters long after the initial stimulus has ceased. In this issue, Gorin et al. (https://doi.org/10.1084/jem.20250976) reveal an unexpected mechanism by which IFN-γ sustains trained immune states through prolonged signaling driven by cytokine retention at the cell surface.