Issues

Celebration of JEM’s 125th Anniversary

Characterization of the human placental macrophages, Hofbauer cells, and their role in maternal–fetal interface

Midgestation induces inflammasome signaling in placental trophoblasts to promote fetal and maternal antimicrobial defense during pregnancy. The placenta is thus a dynamic immunological organ.

CD8⁺ T reg cells play an important role in the maintenance of self-tolerance and can inhibit the development of autoimmune disease. In this issue of JEM, Mishra et al. reveal that TGF-β signaling and an Eomes-dependent genetic program contribute to CD8 T reg cell differentiation and function.

Improving immunotherapies for cancer requires a fundamental understanding of tumor resistance mechanisms. This review examines how single-cell RNA sequencing has transformed the understanding of basic cancer and immune biology in the context of cancer immunotherapy.

Gerhard et al. reveal the conservation of human tumor-infiltrating dendritic cell states via meta-analysis of scRNA-seq datasets. They further explore dendritic cell state conservation in mice and the origins, behavior, and functions of these cells.

Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. This review discusses current knowledge about the advances in understanding lipid metabolism regulation in cancer cells and introduces therapies that disrupt lipid metabolism for cancer treatment.

Building on the status quo of metastasis research, this review highlights key bottlenecks in the spatiotemporal progression of metastasis and provides a framework for propelling bench-to-bedside translation of fundamental preclinical discoveries.

Tertiary lymphoid structures, adjacent to tumor nests, are sites where antitumor adaptive T and B cell immune responses are generated. Fridman et al. highlight the impact of B cells and the antibodies they produce in tumor immunity and a patient’s response to immunotherapy.

Immune-related adverse events (irAEs) are critical limitations to cancer immunotherapy. Understanding mechanisms driving irAEs is critical to their prevention. Here, the authors discuss several hypotheses, the testing of which may improve patient outcomes.

Pain is a common manifestation of sickle cell disease (SCD). Here, the authors report that nociceptors involved in pain perception can protect SCD mice from acute vaso-occlusion through the secretion of CGRP. These results raise the possibility that the manipulation of nociception is a promising therapy for SCD.

By characterizing gut microbiome composition across 946 healthy donors, Byrd et al. demonstrate strong influences of age and biological sex. Additionally, they define global shifts in the gut microbiome composition of patients with non-gastrointestinal tumors compared with healthy donors.

Mast cells (MCs) comprise two lineages that differ in tissue localization and ontologic origin. Derakhshan et al. define the transcriptomes of these lineages during airway inflammation, identifying distinct programs associated with each lineage and a role for TGF-β signaling in inducible MC development.

Hofbauer cells are primitive placental macrophages with a unique phenotype and role in fetal defense. Using transcriptomic and proteomic data, Thomas et al. analyze human first-trimester placental macrophages and delineate markers that identify them. They also reveal that Hofbauer cells have microbicidal capacity, providing the fetus with an additional layer of protection from certain microbes.

Immune profiling of secreted factors from human placentas across gestation identifies inflammasome hyperactivation in placental trophoblasts resulting in constitutive IL-1β and IL-18 secretion. Trophoblast-secreted IL-1β primes circulating monocytes for inflammasome activation and is important for control of placental Listeria monocytogenes infection.

In contrast to well-studied CD4⁺ T reg cells, the molecular mechanisms controlling CD8⁺ T reg cells remain largely elusive. Here, the authors find that TGF-β signal and transcription factor Eomes cooperate to promote the function, location, and homeostasis of CD8⁺ T reg cells.

Tan et al. provide novel insights into understanding how PD-1 regulates regulatory T (T reg) cells. More specifically, this study demonstrates that loss of PD-1 on T reg cells leads to enhanced T reg cell suppressor function in vitro and in vivo. These findings have clinical relevance for understanding the efficacy of PD-1– and PD-L1–mediated checkpoint blockade.

Macaque recipients of anti–HIV-1 combination NAb treatment starting on PI day 3 or week 2 generate CD8⁺ cellular immunity that maintains durable suppression of SHIV replication and circulating CD4⁺ T cell levels during a 3–6-yr observation period.

Paik and Farber demonstrate that lung-localized T cell–mediated protection to heterosubtypic influenza challenge requires priming of new effector T cells in the lung-draining lymph node, which is fortified by increased numbers of dendritic cells from prior influenza infection.

Helicobacter pylori is a pathogenic bacterium causing gastritis and malignancy; however, the underlying mechanism is not fully understood. Nagata et al. purify and identify virulent metabolites of H. pylori modified from host lipid that exacerbate inflammation through C-type lectin receptors.

A novel transgenic mouse, in which the transcription factor NFATc1 bears lysine-to-arginine mutations that prevent modification by SUMO, develops normally and is healthy. However, SUMO-insensitive NFATc1 transmits strong tolerogenic signals, thus preventing autoimmune and alloimmune T cell responses.

Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) and Golgi apparatus of antibody-producing cells, reduced antibody secretion, and aberrant IgG N-glycosylation. The data uncover a key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.

Spatiotemporally restricted endothelial cell calcium influx along with CaM and CaMKIIδ function are required for leukocyte diapedesis. Pharmacologic and genetic approaches show that disruption of this pathway significantly affects inflammation in vitro and in vivo.

Inoue et al. show that a small population of germinal center–derived CD38^intBcl6^hi/intEfnb1⁺ cells with lower mTORC1 activity favors a memory B cell fate. This population also has higher levels of Bcl2 and surface BCR that, in turn, contributes to their survival and development.

Lee-Chang et al. explore the B cell–based vaccine as immunotherapy to treat deadly tumors, including glioblastoma. Their approach utilizes 4-1BBL⁺ B cells as a cellular platform to promote antitumor immunity.

G12C inhibitors (G12C-Is) have significant but limited efficacy in KRAS-mutant malignancies, mostly due to “adaptive resistance.” Combining SHP2 inhibitor (SHP2-I) with G12C-I abrogates adaptive resistance; evokes beneficial, tumor-specific changes in the immune microenvironment; and potentiates PD-1 blockade. SHP2-I also has direct, context-dependent effects on tumor vasculature.

Microglia is a major phagocytic cell type in the brain; however, the underlying mechanism of phagocytosis regulation in microglia is unclear. Ren et al. discovered that Qki in microglia is greatly induced by demyelination and that Qki is an essential regulator of phagocytic activity in microglia.

Mimouna et al. use functional and transcriptomic approaches in a mouse model of multiple sclerosis to show that a transcriptional coregulator, GRIP1, known for anti-inflammatory actions, promotes macrophage- and microglia-driven neuroinflammation but also mediates therapeutic efficacy of type I IFN.

Bassil et al. model the crosstalk of α-syn and tau under copathology conditions. They show evidence of α-syn–dependent tau pathology in the human brain. Moreover, they demonstrate the role of α-syn in the modulation of tau pathology in mice.

This study demonstrated that histamine H₂ receptor in oligodendrocytes negatively regulates its differentiation and remyelination in neonatal hypoxic-ischemic white matter injury through acting on the Wnt/β-catenin signaling pathway. The H₂ receptor antagonists may have potential therapeutic value for neonatal hypoxic-ischemic encephalopathy.