ON THE COVER
Song et al. report that in vivo the R47H variant of TREM2 displays partial loss of function and is unable to restore amyloid-β– induced microgliosis and microglial activation in the AD model mice. The image illustrates the microglia in their resting (elongated) and activated (round) state. Artwork by Emilie Clark (Emilie@emilieclark.com). See page 745.
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Predicting AID off-targets: A step forward
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.
Metaplastic Cdx2-depleted cells can be very disruptive neighbors
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.
Modeling the human bone marrow niche in mice: From host bone marrow engraftment to bioengineering approaches
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.
Brief Definitive Report
Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism
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.
A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets
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.
Sustained Id2 regulation of E proteins is required for terminal differentiation of effector CD8+ T cells
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.
Contextual control of skin immunity and inflammation by Corynebacterium
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.
Atypical chemokine receptor 4 shapes activated B cell fate
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.
Deficiency in T follicular regulatory cells promotes autoimmunity
Fu et al. analyze Bcl6fl/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.
Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity
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.
Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines
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.
Rapid activation of tumor-associated macrophages boosts preexisting tumor 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.
Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor 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.
Therapeutically targeting tumor microenvironment–mediated drug resistance in estrogen receptor–positive breast cancer
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.
The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
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.
BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions
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.
GPR56/ADGRG1 regulates development and maintenance of peripheral myelin
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.
Sox7 promotes high-grade glioma by increasing VEGFR2-mediated vascular abnormality
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.
Technical Advances and Resources
Optimized RNP transfection for highly efficient CRISPR/Cas9-mediated gene knockout in primary T cells
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.
Correction: Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease