Issues

Xiaoyu Hu is a professor and director of the Institute for Immunology at Tsinghua University. Her lab is interested in understanding the molecular mechanisms underlying the transcriptional, translational, and metabolic mechanisms of the key cell types involved in host defense and inflammatory responses: macrophages and intestinal epithelial cells.

In this issue of JEM, Lyons-Cohen et al. reveal that lymph node macro-clusters provide a spatial niche where CD301b⁺ cDC2s and CD4⁺ T cells interact, promoting Th2 responses.

Meningeal lymphatics are conduits for cerebrospinal fluid drainage to lymphatics and lymph nodes in the neck. In this issue of JEM, Boisserand et al. provide evidence that expansion of meningeal lymphatics protects against ischemic stroke.

Leptomeningeal metastasis (LM), or spread of cancer to the cerebrospinal fluid (CSF) and linings of the brain, is a fatal complication of cancer. In this Review, Freret and Boire describe the anatomy of the leptomeninges and routes of cancer spread to the CSF, highlighting therapeutic opportunities.

Cellular senescence is a stress-inducible terminal cell-cycle arrest program with far-reaching pathophysiologic implications. This Review summarizes the evidence that senescent cells need to actively maintain their arrest machinery and discusses the consequences if these epigenome-remodeled cells resume proliferation in a “post-senescent” condition.

Milling et al. report an experimental and analytical framework for performing in vivo CRISPR screens in immune cells. As a proof-of-concept, they demonstrate the utility of incorporating unique molecular identifiers into CRISPR screen libraries for improving statistical power and tracking clonal dynamics.

The authors show that early Th2 cell differentiation is driven via prolonged T–DC macro-clustering in lymph nodes and occurs in a skin site-specific manner. Enhanced costimulatory molecule expression by cDC2 promotes prolonged T cell activation, integrin-dependent macro-clustering, and optimized cytokine sensing.

Intrathecal VEGF-C pretreatment promotes lymphatic drainage of brain-derived fluids and improves neurological outcomes after ischemic stroke via reduced microglia-mediated neuroinflammation and increased BDNF signaling.

This manuscript shows that in the absence of cholesterol 25-hydroxylase (Ch25h) and the resultant reduction in 25-hydroxycholesterol, age-dependent neuroinflammation and neurodegeneration are strikingly reduced in a mouse model of tauopathy.

The study unveils that potent combination therapies remodel TAMs to antitumor proinflammatory M1-like macrophages crucial for their therapeutic efficacy. It demonstrates a positive feedback loop between intratumoral effector T cells and TAMs, mediated by IFN-γ reshaping the tumor microenvironment.

The peripheral activity of anti-PD-1 mAb is not fully understood. Here, Ruggiu, Guérin et al. demonstrate that anti-PD-1 mAb promotes CD8⁺ T cell responses in tumor-draining lymph node by targeting Tfh cells and stimulating IL-4 production.

This research dissects diffuse-type gastric adenocarcinoma (DGAC), an aggressive and therapy-resistant cancer, and unveils that CDH1/E-cadherin inactivation is associated with EZH2 activation and a distinct tumor immune profile, proposing a new molecular subtype of DGAC.

Cavagnero et al. use single-cell transcriptomics to identify dermal immune acting fibroblast (IAF) subsets that communicate with neutrophils during type 17 inflammation. Fibroblast-specific deletion of Il17ra in mice and analysis of human skin following anti–IL-17 demonstrate that such CXCL12+ IAFs play an important role in neutrophil recruitment.

Liu et al. describe a new B cell–intrinsic mechanism underlying increased lupus risk in individuals carrying loss-of-function mutations in NADPH oxidase (NOX2) genes. Mechanistically, reduced NOX2 activity in B cells disrupts endolysosomal trafficking, resulting in amplified Toll-like receptor (TLR) signals and the propensity to humoral autoimmunity.

Zhang et al. reveal a role for hypomorphic SH2B3 in lupus risk. The study shows that rare, damaging variants in lupus patients enable breach of B cell immune tolerance checkpoints and suggests involvement for dysregulated IL-4R signaling and BAFF-R expression.