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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.

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 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.

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.

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.

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.

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 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.

Technical Advances and Resources

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.

Review

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.

Insights

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.

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.

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