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Issues

Insights

In this issue of JEM, Zhang et al. identify a dependency of glioma stem cells on tyrosine phosphatase activity of EYA2 and a new role for this phosphatase at the centrosome, offering a new therapeutic approach to target mitotic activity in glioblastoma.

Reviews

Host-Pathogen Interactions Focus

Toxoplasma gondii is a clinically relevant organism that teaches lessons broadly relevant to host–pathogen interactions. This review highlights how this organism is detected and how the cytokine IFN-γ promotes control of vacuolar pathogens. This article also evaluates the diverse strategies used by T. gondii to evade antimicrobial responses and develop latency.

Brief Definitive Reports

Distinct types of cytokine storms aggravate respiratory viral infection. This study shows that in severe influenza, TLR7 antagonist treatment ameliorates both type I interferon–driven and interferon-independent immunopathology by blocking TLR7-dependent cytokine production by immune cells, without affecting RIG-I–dependent responses in lung epithelia.

This study demonstrates that altering the maternal microbiome impacts the neonatal immune response to respiratory syncytial virus. Using cross-fostering experiments, the authors demonstrate that both prenatal and postnatal factors contribute to protection, including changes in milk metabolites that protect from harmful inflammation.

IL-27 is a pleiotropic cytokine that plays important immunological roles in many disease settings. This study demonstrates that in addition to its known regulatory properties in preventing immune hyperactivity, gut epithelial IL-27 confers barrier immunity through promoting a distinct intraepithelial lymphocyte population.

This study characterizes a Cyp2u1/ mouse model and connects neurodevelopmental deficits to mitochondrial dysfunctions and folate, which could be prevented by folate supplementation in a mouse model. It also validates biochemical and imaging biomarkers in SPG56 patients, which are critical to allow drug development.

TGF-β signaling is indispensable for both Th17 and Treg cell differentiation. We show that Arkadia, an E3 ubiquitin ligase acting in TGF-β signaling, is selectively required for the differentiation of iTreg, but not Th17, cells both in vitro and in vivo.

Articles

Zhang et al. demonstrate EYA2 as a novel therapeutic target in glioblastoma stem cells with localization to the centrosome to promote mitotic spindle function and self-renewal. Inhibitors of EYA2 tyrosine phosphatase activity display selective therapeutic benefit for glioblastoma.

Hermann et al. reveal a lifestyle-independent sex disparity in liver metastasis and survival of pancreatic cancer caused by TIMP1. Increased TIMP1 expression in males predicts liver metastasis in various cancer entities. Such insight into the basis of sex differences substantiates the necessity of considering sex in cancer medicine.

Blockade of CD47 signaling enhances the anti-tumor effects of intratumoral STING stimulation by activating monocyte/macrophage phagocytosis and tumor-specific T cells. This combination therapy induces systemic anti-tumor immune responses, which rely on STING and type I IFN signaling.

Bittner et al. discovered that direct phosphorylation of the inflammasome sensor NLRP3, by the well-established drug target Bruton’s tyrosine kinase (BTK), promotes inflammasome assembly and boosts IL-1β release. NLRP3 phosphorylation by BTK may thus represent a novel target for therapeutic intervention in inflammation.

A novel preclinical mouse model harboring an activating mutation in Gucy2c demonstrates features seen in patients with familial GUCY2C diarrhea syndrome. Fecal microbiome changes and colonic gene expression identify cell intrinsic and extrinsic roles of cGMP in gut inflammation.

Hausmann et al. describe a sentinel intercrypt macrophage population in the intestine, which detects Gram-negative microbes breaching the epithelial barrier and elicits epithelial NF-κB signaling in neighboring crypts. The tunability of this crypt-scale response allows the induction of appropriately scaled defenses according to the localization and intensity of microbial triggers.

Li et al. show with a new assay that NFKB1 variants disrupting the transcriptional activity of RELA-p50 dimers underlie an autosomal dominant form of common variable immunodeficiency by haploinsufficiency, thereby providing a functional approach to test new NFKB1 variants.

Kreye et al. report the isolation of human monoclonal GABAAR antibodies and demonstrate their direct pathogenicity in vitro and in vivo independent of Fc-mediated effector functions. These encephalitis patient-derived antibodies explain the clinical phenotype and can expedite the development of selective immunotherapies.

Aire is a master of central tolerance. Goldfarb et al. compare mice with recessive or dominant-negative Aire patient mutations to dissect the mechanisms that underlie dominance and identify an autoregulatory mechanism by which Aire negatively modulates its own expression.

The network properties of miRNA regulation can be leveraged to discover coregulated genes and pathways that converge on shared biological functions. Wigton et al. uncover an miR-221/222–regulated circuit of transcriptional and epigenetic modulators of class switch recombination.

Circulating skin-derived T cells with TRM phenotype (cTRMs) form a distinct population in blood after hematopoietic stem cell transplantation. cTRMs maintain their skin identity, are increased in GVHD, and display a Th2-like cytokine profile contributing to systemic GVHD inflammation.

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