ON THE COVER
Sayin et al. describe the spatial distribution and functional characteristics of T follicular regulatory (Tfr) cells in human lymph nodes. The cover is a confocal image of Tfr cells within a germinal center from a human mesenteric lymph node. The image was taken from the original manuscript and modified by the JEM editorial office. See page 1531.
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Ma et al. show that removal of cholesterol from CD8 T cells during type 9 differentiation increases their IL-9 production, persistence in vivo, and cytolytic function against tumors by preventing SUMOylation of liver X receptors.
Brief Definitive Report
Intestinal macrophages represent the last tissue macrophages thought to entirely adhere to van Furth's decades-old continuous monocyte replenishment model. In this study, Shaw et al. identify a population of intestinal macrophages that are long lived and maintained independently of monocyte replenishment over long periods of time.
Inflammasomes promote interleukin (IL)-1β secretion and pyroptosis. Kanneganti et al. now show that the pyroptosis effector gasdermin D (GSDMD) is required for systemic IL-1β secretion and autoinflammatory pathology in a mouse model of Familial Mediterranean Fever (FMF), suggesting GSDMD inhibitors as potential antiinflammatory treatments.
Sayin et al. describe the spatial distribution and functional characteristics of T follicular regulatory (Tfr) cells in human lymph nodes. Contrary to existing paradigms, Tfr-mediated suppression appears to be most efficient at the T-B border and within the follicle, not in the germinal center.
Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses
Loss-of-function mutations of the human postsynaptic cell-adhesion protein neuroligin-4 have been repeatedly associated with autism, but the precise synaptic function of neuroligin-4 that may account for its role in autism remains unclear. Here, we show in murine brainstem synapses that neuroligin-4 is selectively required for glycinergic synaptic transmission in mice.
CD8+ T cells can be polarized into IL-9–secreting (Tc9) cells. Ma et al. show that Tc9 cell differentiation is associated with a low cholesterol reprogramming profile, and manipulating cholesterol content in polarizing Tc9 cells significantly affects Tc9 differentiation and antitumor response.
Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses
Pardi and colleagues report on a vaccine platform in which purified, antigen-encoding, nucleoside-modified mRNA is encapsulated in lipid nanoparticles. Immunization with this vaccine elicits potent T follicular helper cell, germinal center B cell, and protective, neutralizing antibody responses.
Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity
Kadelka et al. show that parameters linked with HIV-1 broadly neutralizing antibody (bnAb) development shape HIV-1–binding antibody responses in an antigen and IgG subclass dependent manner. Identified HIV-1 antibody signature landscapes reveal a shift toward IgG1-driven responses in bnAb developers.
We demonstrate that the quantity of IL-7 and Notch signaling differentially regulate lymphocyte fate. We also identify ILC progenitor and immature ILC2 in the fetal mesentery, which are terminally differentiated and matured by PDGFRα+gp38+ mesenchymal cells.
Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia
Peripherally derived macrophages can engraft the brain in the context of chronic microglia loss without brain irradiation and maintain a unique transcriptional signature throughout different experimental contexts.
Reichenbach et al. show that long-term P2Y1-receptor inhibition normalizes cerebral network dysfunction in an Alzheimer’s disease mouse model. This network recovery restores functional and structural synaptic integrity as well as learning and memory, establishing P2Y1-receptor inhibition as a novel potential treatment target.
Du et al. demonstrate that PKCδ modulates BACE1 expression and amyloidogenic amyloid precursor protein processing. Inhibition of PKCδ markedly reduces BACE1 expression, β-amyloid levels, and amyloid plaque formation and also rescues cognitive deficits in Alzheimer disease mouse models.
Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis
Cao et al. show that UGT8 promotes BLBC progression through activating sulfatide–αVβ5 axis. ZA is identified as a direct inhibitor of UGT8 and suppresses BLBC progression, suggesting that inhibition of UGT8 offers a promising opportunity for treating BLBC.
Schmidt et al. propose a new concept for colon cancer therapy that advocates specific and simultaneous targeting of different tumor cell subpopulations with high NOTCH- and MAPK-signaling pathway activity. This overcomes treatment resistance by tumor cell plasticity and strongly improves therapy response.
IL1RAP is an emerging target for AML therapy. Studying its cell-intrinsic function revealed that IL1RAP interacts with and amplifies signaling through c-KIT and FLT3 in AML cells. This novel promiscuous role of IL1RAP in AML has implications for therapeutic targeting.
Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation
Nagase and Inoue et al. generated a novel Asxl1 mutant mouse model to mimic clonal hematopoiesis and myelodysplastic syndromes caused by ASXL1 mutations and elucidated the effects of mutant versus wild-type ASXL1 on hematopoiesis, gene expression, and chromatin state.
Parisotto et al. demonstrate that ablation of the tumor suppressor gene PTEN in prostatic luminal epithelial cells of adult mice stimulates their proliferation, induces replication stress and a DNA damage response, followed by growth arrest with characteristics of cell senescence.
Correction: Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity