ON THE COVER
Zhang et al. report that the S198P mutation in APP promotes accelerated folding and egress to late compartments leading to enhanced Aβ production and deposition in vivo. The cover shows an immunofluorescence image of a brain stained for Iba1 (red), 3D6 (green), and DAPI (blue) to determine the level of microgliosis. Image © Zhang et al., 2021. https://doi.org/10.1084/jem.20210313
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Alzheimer mutant speeds APP transport
Zhang et al. identify a mutation in the APP ectodomain in exon 5, APPS198P, that accelerates folding in the endoplasmic reticulum and transport through the Golgi network to late vesicular compartments, enhancing the accumulation of Aβ aggregates.
Familial thrombocytopenia: The long and short of it
Wahlster et al. describe a multigenerational family with inherited thrombocytopenia. Long-read sequencing and RNA sequencing revealed a complex structural variant, causing overexpression of a pathogenic gain-of-function WAC-ANKRD26 fusion transcript.
Immune cells—A curse and a blessing!
Innate immune cells are crucial in the development and regulation of cardiovascular disease. In this issue, two groups, Davis et al. and Li et al., describe the impact of the innate immune system on the development of cardiovascular disease.
The discovery of dendritic cells
An excerpt from Ralph Steinman’s Harvey Lecture describing the discovery of dendritic cells.
Taking regulatory T cells into medicine
Shimon Sakaguchi recounts the work that lead to the identification of regulatory T cells.
Ferroptosis in infection, inflammation, and immunity
In this review, the authors focus on ferroptosis in innate and adaptive immunity. They also discuss and highlight the impact of ferroptotic death in infection, inflammation, and immune diseases.
SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?
SARS-CoV-2 is the trigger of MIS-C, which suggests that other viruses may trigger different forms of Kawasaki disease. The discovery of inborn errors of immunity underlying MIS-C would facilitate that of inborn errors of immunity to viruses underlying Kawasaki disease.
Brief Definitive Reports
Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript
Wahlster, Verboon, et al. identify and functionally characterize a complex structural variant in a family with thrombocytopenia that results in a WAC-ANKRD26 fusion transcript encoding a shortened form of ANKRD26, whose expression during hematopoiesis is deregulated, thereby resulting in disease.
Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation
Vijay et al. identify that phosphatidylserine exposed on dead or dying red blood cell membranes signals via Axl on B cells to promote polyclonal B cell activation and plasmablast differentiation during infections that are associated with hemolysis.
Altered selection on a single self-ligand promotes susceptibility to organ-specific T cell infiltration
Using mice lacking a single self-peptide, the authors show that altered T cell selection on a single self-ligand predisposes mice to organ-specific T cell infiltration. Proper selection directs cells into the regulatory T cell lineage with negligible evidence of deletion.
Human KIT+ myeloid cells facilitate visceral metastasis by melanoma
Colonization of visceral organs with melanoma in humanized NSG-SGM3 mice is dependent upon human CD33+CD11b+CD117+ progenitor cells. A gene signature of KIT/CD117–expressing CD33+ subset correlates with decreased overall survival in TCGA melanoma samples and represents a novel candidate biomarker.
Technical Advances and Resources
STARTRAC analyses of scRNAseq data from tumor models reveal T cell dynamics and therapeutic targets
Single cell RNAseq analyses were performed on T cells from MC38 and CT26 tumor models. PCA-based sub-clustering and STARTRAC analyses revealed fine-tuned T cell subsets and dynamic in tumor. CCR8 was identified as a novel target on Tregs to synergize with anti–PD-1 for cancer immunotherapy.
An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo
The study demonstrates that the S198P mutation in APP promotes accelerated folding and egress to late compartments leading to enhanced Aβ production and deposition in vivo.
PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling
Myocardial ischemia-reperfusion injury generates sterile inflammation sites in which neutrophils are activated and cause myocardial reperfusion injury. During this event, the neuronal guidance molecule netrin-1 is released by activated neutrophils and dampens myocardial inflammation by activating adenosine receptors (ADORA2B) expressed on myeloid immune cells.
Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms
Abdominal aortic aneurysms (AAAs) are a life-threatening disease characterized by macrophage infiltration contributing to pathological vascular remodeling. Herein, we demonstrate that the histone demethylase JMJD3 is a critical regulator of inflammation during AAA development and cell-specific inhibition reduces AAA progression.
IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
Lanz et al. reveal that IFITM3, an effector protein of the IFN response, can compete with influenza virus glycoproteins for incorporation into viral particles. This decrease in viral glycoprotein content sensitizes influenza virus to antibody-mediated neutralization, thereby impacting the severity of influenza disease.
Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors
Higa et al. show that chronic interleukin-1β exposure primes multipotent hematopoietic progenitor cells for myelopoiesis by upregulating myeloid differentiation programs and repressing stem gene programs in a Cebpa-dependent manner. Consequently, interleukin-1 potently selects for Cebpa loss in hematopoietic stem and progenitor cells.
PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress
In this article, Chavez et al. show that the myeloid transcription factor PU.1 plays an essential role in maintaining hematopoietic stem cell (HSC) quiescence and homeostatic protein synthesis rates, thereby regulating HSC pool size and cell cycle activity during chronic inflammatory stress.
Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy
Loe et al. demonstrate dosage-dependent roles of Arid1a, whereby the loss of its single copy promotes tumor progression, but tumor cells lacking both copies exhibit a survival disadvantage. This finding leads to a novel combined targeting approach for the effective inhibition of Arid1a heterozygous tumor cell growth.
Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion
Tumor recurrence is frequent in oral squamous cell carcinomas and leads to poor survival. This study is the first demonstration of the pivotal role of adjacent histologically normal epithelium in lateral invasion, with vital implications for understanding tumor recurrence and field cancerization.
Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia
Cachexia increases morbidity and mortality. Rupert et al. show PDAC cachexia results from tissue crosstalk via an IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6.
Feeding-induced hepatokine, Manf, ameliorates diet-induced obesity by promoting adipose browning via p38 MAPK pathway
This article shows Manf, a feeding-induced hepatokine, can directly promote browning of white adipose tissue via the p38 MAPK pathway and consequently protect mice against high-fat diet–induced obesity.
ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue
The authors demonstrate that loss of ICOS-dependent PI3-kinase signaling supports visceral adipose tissue (VAT) TR abundance and function, and correlates with reduced adipose inflammation and improved insulin sensitivity after a high-fat diet. This highlights a new pathway regulating VAT-TR activity.
Blood leukocytes recapitulate diabetogenic peptide–MHC-II complexes displayed in the pancreatic islets
Assessing the self-antigens causing type 1 diabetes remains challenging. This study shows that blood leukocytes contain immunogenic peptides with compatible sequences to those presented in the pancreatic islets, representing a feasible strategy for probing a target autoimmune tissue.
The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude
ID2 is an essential transcription factor for natural killer cell development. Through epistasis analysis, Li et al. show that ID2 controls the amplitude of TCF1 and allows for its temporal downregulation, thereby supporting natural killer cell maturation.
Ptpn2 and KLRG1 regulate the generation and function of tissue-resident memory CD8+ T cells in skin
Hochheiser et al. identify Ptpn2 and KLRG1 as new regulators of CD103+ CD8+ TRM cells in mouse skin. While KLRG1 inhibits TRM formation, genetic Ptpn2 deficiency increases the protective function of TRM cells in infection but aggravates TRM-dependent autoimmunity.
Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity
The authors show that autophagy in lymphatic endothelial cells (LECs) dampens collagen-induced arthritis by regulating two distinct pathways: the promotion of T reg cells in LNs and the inhibition of S1P-dependent migration of pathogenic Th17 cells in inflamed organs.