ON THE COVER
Moore et al. report short Aβ peptides are not toxic and are protective against Aβ42 toxicity, in a dose-dependent manner, supporting the use of γ-secretase modulators as therapeutics for Alzheimer’s disease. Th e cover illustrates a Drosophila melanogaster eye expressing the short Aβ peptide, Aβ38. The image was provided by the authors and modified by the JEM editorial office. See page 283.
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
In this issue Ohsaki et al. explain how breastfeeding can prevent the onset of food allergies in offspring by instructing T reg formation via neonatal Fc receptor (FcRn)–mediated transfer and uptake of allergen-containing IgG immune complexes (Ig-ICs) by gut dendritic cells (DCs).
In this issue of JEM, Chheda et al. report that a conserved hotspot mutation associated with an aggressive form of brain cancer generates an immunogenic T cell epitope restricted by a common HLA subtype, thereby creating a “public” neoantigen.
In this issue of JEM, Sulciner et al. (https://doi.org/10.1084/jem.20170681) provide evidence that therapy-induced cancer cell death can, paradoxically, stimulate and accelerate the growth of surviving malignant cells by fueling tumor-promoting inflammation. Resolvins, a class of lipid mediators, counteract this effect, representing an attractive target for therapeutic intervention.
In this issue of JEM, Wu et al. use genetic barcoding of macaque hematopoietic stem cells to demonstrate that, after transplantation, HSCs are very asymmetrically distributed and uncover a thymus-independent pathway for mature T cell production in the bone marrow
In this issue of JEM, Kaittanis et al. report a new signaling role for prostate-specific membrane antigen (PSMA), providing a mechanistic link between two major oncogenic pathways, as well as promising therapeutic implications for the diagnosis and treatment of prostate cancer.
Emerging evidence indicates that both innate and adaptive immunity contribute to hypertension. Efforts to understand mechanisms of immune activation in hypertension are defining not only new mechanisms of disease but also new therapeutic options for its treatment.
Petrova and Koh discuss recent progress in understanding organ-specific specialization of lymphatic vasculature, such as discovery of meningeal lymphatic vasculature and perivascular brain lymphatic endothelial cells, hybrid blood-lymphatic identity of Schlemm’s canal, and the mechanisms controlling dietary fat uptake by intestinal lacteals.
Brief Definitive Report
The evolutionarily conserved SIRT1–FoxO1 axis plays a new role in human CD8+ T cell metabolism and function. Progression from the naive to the terminally differentiated memory state is accompanied by the loss of SIRT1 and FoxO1 expression, which derepresses glycolytic and cytotoxic capacities of CD8+CD28– T cells under resting conditions.
Rare PfCSP C-terminal antibodies induced by live sporozoite vaccination are ineffective against malaria infection
Scally et al. show the molecular, structural, and functional characterization of human antibodies against the C-terminal domain of Plasmodium falciparum (Pf) circumsporozoite (CSP [C-PfCSP]) and reveal that its arrangement on the Pf sporozoite surface and epitope polymorphism contribute to poor C-PfCSP immunogenicity and ineffective humoral responses in volunteers protected against Pf malaria.
Whether Ig engagement by antigen is required to initiate somatic evolution and affinity maturation is not well defined. Silver and colleagues show that germinal center flexibility permits nonspecific B cells to achieve de novo antigen recognition and antibody affinity maturation.
Whether maternal immune responses modulate tolerance in association with allergy in offspring is unknown. Ohsaki et al. demonstrate that the neonatal crystallizable fragment receptor mediates transfer and antigen presentation of maternal allergen–IgG immune complex in breast milk and drives regulatory T cell–mediated tolerance in offspring against food allergy.
Cancer therapy reduces tumor burden by killing tumor cells, yet it simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Sulciner et al. demonstrate that specific resolvins (RvD1, RvD2, and RvE1) inhibit tumor growth and enhance cancer therapy through the clearance of tumor cell debris.
Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy
Chheda et al. have identified an HLA-A2–restricted CD8+ T cell epitope encompassing the H3.3K27M mutation and a corresponding TCR that specifically recognizes the H3.3K27M epitope in glioma cells. These data establish a preclinical basis for T cell–based therapy for HLA-A2+ patients with H3.3K27M+ glioma.
Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors
Kaittanis et al. show that the processing of glutamated folates by prostate-specific membrane antigen induces the activation of metabotropic glutamate receptors and initiation of PI3K–Akt signaling in prostate cancer.
Cilia loss is common in cancer, and its roles remain unknown. Deng et al. show that cilia loss sensitizes cells to transformation by activating a mevalonate pathway through β-catenin–TCF signaling. The mevalonate pathway inhibitor statin blocks the progression of pancreatic cancer.
NOTCH1 is an attractive cancer target, particularly in T cell acute lymphoblastic leukemia (T-ALL), with activating mutations in this gene identified in more than 50% of cases. In this study, Roti et al. describe the synthesis, characterization, and validation of JQ-FT, a first-in-class NOTCH1 inhibitor that has dual selectivity for leukemia over normal cells and NOTCH1 mutants over wild-type receptors.
Wu et al. use barcode tracking to uncover prolonged geographic bone marrow segregation of regenerating hematopoietic stem and progenitor cell clones after transplantation and provide evidence for local bone marrow production of T cells.
Eich et al. reveal the dynamic expression of the Gata2 transcription factor in single aortic cells transitioning to hematopoietic fate by vital imaging of Gata2Venus mouse embryos. Pulsatile expression level changes highlight an unstable genetic state during hematopoietic cell generation.
Harly et al. show that early innate lymphoid progenitors (EILPs) are a developmental intermediate between all-lymphoid progenitors (ALPs) and ILC precursors (ILCps) and identify requirements for their generation and further differentiation.
ILC2s are potent mucosal effector cells that participate in type 2 inflammatory responses. Stier et al. demonstrate that IL-33 negatively regulates CXCR4, mediating the egress of ILC2 lineage cells from the bone marrow for potential hematogenous trafficking.
Data demonstrate that short amyloid-β (Aβ) peptides are not toxic in vivo and can partially block toxicity associated with Aβ42 accumulation. Moore et al. further validate the use of γ-secretase modulators that lower Aβ42 and increase short Aβs as potential Alzheimer’s disease therapeutics.
Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. Tirone et al. show that alternative redox forms of high mobility group box 1 (HMGB1), the “alarmin” signal released by damaged cells, trigger inflammation or tissue repair after injury by interacting with distinct receptors and that a nonoxidizable HMGB1 mutant promotes regeneration without exacerbating inflammation.
RAF/MEK/extracellular signal–related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions
Hogstad et al. show that the somatic BRAFV600E mutation in myeloid dendritic cell precursors in Langerhans cell histiocytosis promotes lesion formation through impaired dendritic cell migration and resistance to apoptosis, which can be rescued with targeted MAPK pathway inhibition.
Weinstein et al. demonstrate that the transcription factors T-bet and STAT4 are necessary for Tfh cell expansion with secretion of IFN-γ and IL-21 and consequent robust germinal center output during acute viral infection.
Mannose receptor high, M2 dermal macrophages mediate nonhealing Leishmania major infection in a Th1 immune environment
Lee et al. demonstrate that mannose receptor–mediated infection of M2-like dermal macrophages plays a critical role in nonhealing cutaneous infection by L. major. The dermal macrophages are radio resistant and self-renewed and efficiently maintain their M2 phenotype during Th1 immunity.
Correction: Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors