Issues

In this issue of JEM, Álvarez-Prado et al. designed a DNA capture library allowing them to identify 275 genes targeted by AID in mouse germinal center B cells. Using the molecular features of these genes to feed a machine-learning algorithm, they determined that high-density RNA PolII and Spt5 binding—found in 2.3% of the genes—are the best predictors of AID specificity.

In this issue of JEM, Boucher et al. report isolation of active caspase-1 from macrophages after inflammasome activation. Surprisingly, they find that caspase-1 is quickly inactivated upon autoproteolytic processing.

In this issue of JEM, Balbinot et al. describe an original mechanism where Cdx2 inactivation regulates intestinal metaplastic to neoplastic transition in a paracrine fashion. Surprisingly, the target cells are neighboring “normal” Cdx2-positive cells.

Abarrategi et al. summarize the methods used for human hematopoietic cell xenotransplantation and their milestones. They also discuss the latest approaches in generating humanized BM tissues in mice to study human normal and malignant hematopoiesis.

The R47H variant of the microglia gene TREM2 has been linked to a significantly higher risk of Alzheimer’s disease. In this study, Song et al. generate human TREM2-expressing mice and demonstrate that R47H leads to a decreased microglia number and activation as well as a decreased presence of soluble TREM2 on neurons and plaques in a mouse model of Alzheimer’s disease.

Álvarez-Prado et al. report a detailed map of AID-induced off-target mutations and identify molecular features that predict gene mutability. They identify a novel AID hotspot and demonstrate that base excision and mismatch repair back up each other to repair most AID deamination events.

CD8⁺ T cells responding to infection differentiate into short-lived effector cells destined to die or memory cells that provide long-lived protection. Omilusik et al. demonstrate that commitment to an effector cell fate is not necessarily terminal and that sustained transcriptional regulation is required to maintain subset-specific properties.

Belkaid et al. show that Corynebacterium, a dominant skin microbe, promotes activation of γδ T cells in a mycolic acid–dependent manner without altering skin homeostasis. Such effect promotes inflammation in the context of high-fat-diet and psoriasis-like settings.

Kara et al. show that ACKR4 regulates early activated B cell differentiation fate. ACKR4 limits the early proliferation of activated B cells by restricting their initial access to the splenic interfollicular zone.

Fu et al. analyze Bcl6^fl/flFoxp3Cre/Cre mice and show that Tfr deficiency enhances immunity to influenza virus but promotes autoimmunity, which sheds new light on the understanding and treatment of autoimmune diseases.

The inflammasome generates caspase-1 p20/p10, presumed to be the active protease. Boucher et al. demonstrate that the inflammasome contains an active caspase-1 species, p33/p10, and functions as a holoenzyme. Further caspase-1 self-processing generates and releases p20/p10 to terminate protease activity.

CTLA4 insufficiency is genetically associated with stomach cancer. Miska et al. demonstrate that CTLA4 insufficiency causes stomach cancer by autoimmune inflammation, an effect largely attributed to type 2 cytokine stimulation of stomach mucosal cells. These findings suggest preventive strategies against tumor initiation by controlling type 2 inflammation while preserving type 1 immunity.

Combined CSF-1R+CD40 antibody therapy induces profound and rapid TAM reprogramming before TAMs are eliminated. This combination of cancer immunotherapies tailored to activate the innate immune system creates an inflamed tumor microenvironment ultimately leading to tumor eradication by the adaptive immunity.

Perry et al. show that myeloid-targeted immunotherapy with a combination of anti-CD40 and CSF-1R inhibition synergistically induces a proinflammatory microenvironment that suppresses CPI-resistant tumors in a TNF-α– and IFN-γ–dependent manner.

Tumor microenvironment (TME) cytokine screening revealed FGF2 as a clinically relevant mechanism of resistance to anti-estrogens, mTORC1 inhibition, and PI3K inhibition in ER+ breast cancer. Shee et al. highlight an underdeveloped aspect of precision oncology: treating patients according to their TME constitution.

Balbinot et al. show that intestinal epithelial cells depleted in the homeobox gene Cdx2 acquire an imperfect gastric-type metaplastic phenotype that, through changes in the microenvironment, induces the tumorigenic evolution of adjacent Cdx2-intact cells without themselves becoming cancerous.

This study uses mouse models to answer how BACE1 inhibitory drugs will be beneficial to Alzheimer’s patients. Hu et al. find that sequentially increased deletion of BACE1 in one adult Alzheimer’s mouse model reverses preexisting amyloid plaques and mitigates synaptic failures.

This study identifies GPR56/ADGRG1 as a conserved regulator of peripheral nervous system myelination and defines a novel interacting partner of GPR56: plectin. This study is directly relevant to human health because mutations in GPR56 and PLECTIN cause diseases with neuropathic symptoms.

Antiangiogenic therapy has a clinical benefit in only a subpopulation of high-grade glioma (HGG) patients. Kim et al. show that in an orthotopic HGG model, high levels of Sox7 in tumor vessels correlate with improved survival by anti-VEGFR2 antibody, suggesting a potential mechanism of heterogeneous therapeutic outcome to antiangiogenic therapy.

Seki and Rutz describe an optimized Cas9/RNP transfection approach to enable highly efficient CRISPR-mediated gene knockout in primary mouse and human T cells without T cell receptor stimulation that results in near complete loss of target gene expression at the population level.