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Chun-Hao Chen et al.
Nerves are integral to adenoid cystic carcinoma (ACC). We identified sympathetic nerves in ACC that promote disease progression and correlate with worse patient survival. Sympathetic nerves reflect tumor axonogenesis driven by noradrenergic neural development programs, and can be targeted as a therapeutic strategy.
Brief Definitive Report
Aleksej Frolov et al.
Frolov et al. discover an expansion and activation of microglia and T cells preceding neuronal loss in spastic paraplegia 15, highlighting the importance of immune responses and myeloid cell–lymphocyte interactions in the pathogenesis of hereditary spastic paraplegias.
Article
Katrin F. Nickel et al.
Factor XII drives thrombosis but is dispensable for hemostasis, making it an anticoagulant drug target. This study shows that factor XII–triggered coagulation traps pathogens and limits bacterial dissemination, highlighting a role of prothrombotic mechanisms in innate immunity and host defense.
Article
Seth D. Fortmann et al.
Fortmann et al. unravel the immune landscape of the human choroid in health and AMD. They demonstrate that a previously unknown prenatally derived macrophage is uniquely involved in lipid metabolism and vascular maintenance and is decreased and dysfunctional in AMD.
Technical Advances and Resources
Minoru Matsumoto et al.
This study highlights the contribution of PRC2 to Aire-mediated stochastic gene expression and the development of mimetic cells through various single-cell approaches. The genomics data utilized in this work serve as a valuable resource for advancing research on Aire.
Brief Definitive Report
Fanny Saidoune et al.
Chilblains were reported in SARS-CoV-2–exposed individuals without PCR- or serologically defined COVID-19. Excessive TLR7 responses to SARS-CoV-2 by pDCs are linked to I-IFN–driven chilblain development. While TLR7 deficiency predisposes to severe COVID-19, enhanced TLR7 responses may confer sterilizing immunity to SARS-CoV-2, with chilblains as a trade-off.
Brief Definitive Report
Nicolas Fonta et al.
Oligodendrocyte-derived IL-33 regulates self-reactive CD8+ T cells in CNS autoimmunity. IL-33 ablation reduces persistence and TCF-1low effector T cell generation, mitigating disease. Local IL-33 blockade via delivery of a decoy receptor improves outcomes, highlighting tissue factors as druggable targets for chronic CNS autoimmune disorders.
Journal of Experimental Medicine Cover Image for Volume 222, Issue 4
Current Issue
Volume 222,
Issue 4,
7 April 2025
Reviews & Opinions
Review
Hanover C. Matz, Ali H. Ellebedy
Influenza virus remains a public health burden for which recommendations encourage annual vaccination. However, some studies have suggested repeat annual vaccination may have negative effects on influenza virus immunity. This review analyzes immunological mechanisms that may result in reduced effectiveness of annual influenza virus vaccines.
Review | Cancer Focus
Andrew A. Almonte et al.
We highlight how the gut microbiome modulates immune checkpoint blockade efficacy in cancer. We outline diagnostic tools for dysbiosis, examine microbiota-centred interventions (e.g., faecal microbiota transplantation, probiotics, dietary changes), and propose clinical strategies. This review underscores their potential to improve ICB outcomes and reduce toxicity.
Viewpoint
Ofer Levy
Ofer Levy, Director, Precision Vaccines Program at Boston Children’s Hospital, reflects on implications of the new FDA Modernization Act 2.0 on accelerating drug and vaccine discovery and development.

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