Journal of Experimental Medicine最新文献

Interferon regulatory factors (IRFs) are a family of transcription factors essential for immune system development and host defense. Beyond immunity, IRF6 plays an indispensable role in craniofacial development. Inborn errors of IRFs (IE-IRFs) are a group of rare monogenic disorders caused by damaging variants in the IRF family of genes. In this review, we comprehensively discuss known IE-IRFs and how they contribute to our understanding of human biology, and provide a framework for their diagnosis and treatment. The IRF transcription factors mediate a wide range of biological functions. Accordingly, genetic defects in individual IRFs give rise to diverse human phenotypes, including increased susceptibility to infection, impaired immune development, and even congenital anatomical anomalies. Our collective understanding of IE-IRFs is a powerful example of how integration of clinical care with mechanistic translational research can transform the lives of patients while simultaneously advancing our fundamental understanding of human biology.

Metastatic progression is a major cause of radiotherapy (RT) failure, yet the mechanisms linking RT to immune suppression and metastasis remain unclear. Here, we identify YTHDF2 as a radiation-induced immune checkpoint in dendritic cells (DCs). By analyzing patient biopsies from a clinical trial (NCT03223155), we discover that increased YTHDF2 expression in DCs after RT correlates with treatment failure after RT. Mechanistically, ionizing radiation induces SPI1, which drives transcription of Ythdf2 in DCs. Upregulated YTHDF2 promotes m6A-mediated degradation of Notch pathway regulators (Mfng, Aph1b, Aph1c), impairing MHC-I cross-presentation and CD8+ T cell activation, thereby facilitating tumor immune evasion and metastatic spread. Crucially, targeting YTHDF2 restores DC immunogenicity, enhances RT-induced tumor control, and improves DC-based cancer vaccines when combined with RT, providing a clinically actionable strategy to overcome RT resistance and metastasis.

Apoptotic cell (AC) corpses can be taken up by certain types of dendritic cell (DC), which cross-present dead cell-derived antigens. In this issue of JEM, Tam et al. (https://doi.org/10.1084/jem.20250887) reveal that GPR34, a lysophosphatidylserine receptor, promotes AC uptake and cross-presentation by type 1 DCs (cDC1s).

JAK2V617F causes >50% essential thrombocythemia (ET) and >90% polycythemia vera (PV). How such a single mutation causes distinct disorders remains a long-standing enigma. Here, we show that heterozygous JAK2V617F activates the transcription factor aryl hydrocarbon receptor (AhR), which biases MEP differentiation toward megakaryocytes in ET patients. In contrast, most PV patients' JAK2V617F exhibits a homozygous mutation that does not activate AhR. We found that JAK2V617F forms a heterodimer with JAK2 to recruit and activate STAT1, thereby inducing AhR activation and driving ET pathogenesis. However, JAK2 forms V617F homodimers in PV patients, which activate STAT5 and drive PV development. In addition to increasing platelet number, activated AhR may enhance platelet activity via the COX2-TXA2 axis. Importantly, targeting AhR inhibits thrombocytosis in JAK2V617F ET humanized mice. These findings not only elucidate the molecular mechanism of JAK2V617F ET but also provide a potential strategy for its treatment.

Currently, it remains largely unclear how MSI-H/dMMR tumors, despite heightened immune pathway activation and antigenic mutation accumulation, evade immune elimination and promote tumorigenesis. Our study showed that dMMR tumors accumulate cytosolic double-stranded DNA, activating the cGAS-IFN pathway and upregulating DNA-digesting enzyme TREX1. In immunocompetent mice, Trex1 depletion in MSI-H/dMMR tumors abolished tumor formation in a CD8+ T cell-dependent manner, suggesting its critical role in enabling these tumors to evade immune attack. Mechanistically, Trex1 loss amplified tumor-intrinsic cGAS-STING signaling, promoted the activation of CD8+ T cells, and triggered systemic antitumor immunity. Critically, ablating cGAS-STING signaling in MSI-H/dMMR tumors abolished the immune boost from TREX1 deletion, revealing the critical role MSI-H/dMMR tumor-intrinsic cGAS-STING pathway. Furthermore, Trex1 inhibition specifically reduced MSI-H/dMMR tumors growth in vivo, highlighting its clinical potential. Together, we identify the cGAS-STING-TREX1 loop as a key immune escape mechanism in MSI-H/dMMR cancers, suggesting TREX1 inhibition could enhance immunotherapy for these patients.

The early immune mechanisms determining Mycobacterium tuberculosis infection outcome are unclear. Using bulk and scRNA-seq over the first weeks of infection, we describe an unexpected, higher early pulmonary type I IFN response in relatively resistant C57BL/6 as compared with highly TB-susceptible C3HeB/FeJ mice. C57BL/6 mice showed pronounced early monocyte-derived macrophage (MDM) accumulation and extensive CD4+ T cell-MDM interactions in lung lesions, accompanied by high expression of T cell-attractant chemokines by MDMs. Conversely, lesions in C3HeB/FeJ mice were dominated by neutrophils with high expression of pro-inflammatory chemokines, from which CD4+ T cells were spatially segregated. Early type I IFN signaling blockade reduced bacterial load and neutrophil swarming within early TB lesions while increasing CD4+ T cell numbers in both C57BL/6 and C3HeB/FeJ mice, with later more pronounced effects on bacterial load in C3HeB/FeJ mice. These data suggest that early type I IFN signaling during M. tuberculosis infection favors neutrophil accumulation and limits CD4+ T cell infiltration into developing lesions.

Whether and where lymphatic vessels occur in bone or bone marrow is unclear. The heterogeneity of skull channels and bone marrow remains poorly understood. Here, we used organ clearing, high-resolution three-dimensional imaging, cell type-specific mouse genetics, and surgical approaches to investigate skull vasculatures. We identified lymphatic vessels at the skull periosteum and found no evidence of lymphatic vessels in the cortical bones or skull bone marrow, where the lymphatic marker VEGFR3 labels blood vessels. Skull periosteum channels to the upper skin are found to occur more frequently in the parietal bone than the interparietal bone, whereas bone marrow is found more often in the interparietal bone than the parietal bone. Despite skull bone marrow expansion during aging, skull channels are significantly reduced, suggesting the aging-dependent uncoupling of skull channels and bone marrow. Together, our findings show lymphatic vessels are present in the skull periosteum but absent in bone marrow, with channel and bone marrow heterogeneity varying by skull region and age.

Mycobacterium tuberculosis drives expression of type I IFN-mediated neutrophil accumulation, which limits interaction between CD4 T cells and macrophages. Failure to limit type I IFN very early in the interaction between Mtb and immune cells allows rapid progression of disease (Branchett et al. https://doi.org/10.1084/jem.20250466; Gern et al. https://doi.org/10.1084/jem.20250161).