Therapeutic discovery for mantle cell lymphoma (MCL) has been hindered by a lack of preclinical mouse models that recapitulate human disease. In this issue, Pieters and colleagues (2021. J. Exp. Med. https://doi.org/10.1084/jem.20202280 ) establish a novel mouse model of MCL driven by overexpression of cyclin D2 and identify fetal-derived B1a cells as putative cell of origin for MCL.

Löfgren’s syndrome is an acute form of sarcoidosis that is characterized by the activation of CD4⁺ T helper cells. In this issue of JEM, Greaves et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210785 ) identified a peptide derived from an airborne mold species that stimulates T cells of Löfgren’s syndrome patients in an HLA-DR3–restricted manner. An increased serum IgG antibody response to the full-length protein was also observed in those patients, indicating that the fungus Aspergillus nidulans might be the elusive microbial agent that drives acute sarcoidosis.

In this issue of JEM, Gschwend et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210745 ) reveal the indispensable role of alveolar epithelial cells type 2 in controlling the density of alveolar macrophages. This study highlights the intricate crosstalk that lung stroma and macrophages undergo to maintain homeostasis.

Interferons establish innate antiviral immunity. Two recent papers in JEM by Lopez et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20211211 ) and Cheemarla et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210583 ) show that an appropriate supply of antiviral interferon enables epithelial cells of the nasopharyngeal mucosa to inhibit SARS-CoV-2 growth and that interferon-induced mucosal genes serve as biomarkers of infection.

Intestinal inflammation, in the absence of infection, occurs from contributions by genetics and environment. Chen et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210324 ) challenge this concept by demonstrating that a dominant transmissible dysbiotic microbial community predisposes to intestinal inflammation in absence of genetic alterations.

A unique experiment in bringing academic and industrial scientists together to tackle endemic infectious diseases has proved a success. The Tres Cantos Open Lab Foundation, guided and advised by independent experts, funds extended stays of academics at the campus of a pharmaceutical company, where they access the firm’s resources in partnership with company scientists. Progress in tackling tuberculosis, protozoal infections, and enteric bacterial diseases has sustained the decade-long evolution of the model, whose distinctive features complement other public–private partnerships with similar goals.

In this issue of JEM, Guo et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20202350 ) examine the importance of tumor-derived astrocytes in SHH-medulloblastoma recurrence. They show that tumor cells transdifferentiate to tumor-derived astrocytes via bone morphogenetic proteins and Sox9, which excitingly can be targeted by BMP inhibitors.

In this issue of JEM, Podstawka et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210409 ) show that B cells can limit neutrophil responses within the lung microvasculature by marginating and acting on marginated neutrophils. This study provides a new view of B cells and reveals a novel mechanism of cell-mediated intravascular regulation.

The NS1 protein of flaviviruses is taking center stage. Recent work has made it an attractive target for development of vaccines and immunotherapeutics. Cavazzoni and colleagues (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210580 ) now reveal a dark side to NS1, linking it to the development of self-reactive antibodies.

Bats are attracting the greatest attention recently as a putative reservoir of SARS-CoV-2 responsible for the COVID-19 pandemic. However, less known to the public, bats also have several unique traits of high value to human health. The lessons we learn from bats can potentially help us fight many human diseases, including infection, aging, and cancer.

The three classes of interferons (IFNs) share the ability to inhibit viral replication, activating cell transcriptional programs that regulate both innate and adaptive responses to viral and intracellular bacterial challenge. Due to their unique potency in regulating viral replication, and their association with numerous autoimmune diseases, the tightly orchestrated transcriptional regulation of IFNs has long been a subject of intense investigation. The protective role of early robust IFN responses in the context of infection with SARS-CoV-2 has further underscored the relevance of these pathways. In this viewpoint, rather than focusing on the downstream effects of IFN signaling (which have been extensively reviewed elsewhere), we will summarize the historical and current understanding of the stepwise assembly and function of factors that regulate IFNβ enhancer activity (the “enhanceosome”) and highlight opportunities for deeper understanding of the transcriptional control of the ifnb gene.

Alzheimer’s disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated this response as progressive conversion of homeostatic microglia into disease-associated microglia (DAM); additional reactive microglial populations have been reported in other models of neurodegeneration and neuroinflammation. We review all of these microglial signatures, highlighting four fundamental patterns: DAM, IFN–microglia, MHC-II microglia, and proliferating microglia. We propose that all reported microglia populations are either just one or a combination, depending on the clustering strategy applied and the disease model. We further review single-nucleus RNA sequencing (snRNA-seq) data from human AD specimens and discuss reasons for parallels and discrepancies between human and mouse transcriptional profiles. Finally, we outline future directions for delineating the microglial impact in AD pathogenesis.

Astrocytes are abundant glial cells in the central nervous system (CNS) that control multiple aspects of health and disease. Through their interactions with components of the blood–brain barrier (BBB), astrocytes not only regulate BBB function, they also sense molecules produced by peripheral immune cells, including cytokines. Here, we review the interactions between immune cells and astrocytes and their roles in health and neurological diseases, with a special focus on multiple sclerosis (MS). We highlight known pathways that participate in astrocyte crosstalk with microglia, NK cells, T cells, and other cell types; their contribution to the pathogenesis of neurological diseases; and their potential value as therapeutic targets.

In obesity complicated by hypertension, multicellular processes integrate to orchestrate cardiac fibrosis; the underlying mechanisms, however, remain elusive. In this issue of JEM, Cheng et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210252 ) describe adipocyte–macrophage collaboration to foster cardiac fibrosis through the actions of angiotensin II in obesity.

Intercellular communication among immune cells is vital for the coordination of proper immune responses. Extracellular vesicles and particles (EVPs) act as messengers in intercellular communication, with important consequences for target cell and organ physiology in both health and disease. Under normal physiological conditions, immune cell–derived EVPs participate in immune responses by regulating innate and adaptive immune responses. EVPs play a major role in antigen presentation and immune activation. On the other hand, immune cell–derived EVPs exert immunosuppressive and regulatory effects. Consequently, EVPs may contribute to pathological conditions, such as autoimmune and inflammatory diseases, graft rejection, and cancer progression and metastasis. Here, we provide an overview of the role of EVPs in immune homeostasis and pathophysiology, with a particular focus on their contribution to innate and adaptive immunity and their potential use for immunotherapies.

Respiratory viral infections present a major threat to global health and prosperity. Over the past century, several have developed into crippling pandemics, including the SARS-CoV-2 virus. Although the generation of neutralizing serum antibodies in response to natural immunity and vaccination are considered to be hallmarks of viral immune protection, antibodies from long-lived plasma cells are subject to immune escape from heterologous clades of zoonotic, recombined, or mutated viruses. Local immunity in the lung can be generated through resident memory immune subsets that rapidly respond to secondary infection and protect from heterologous infection. Although many immune cells are required to achieve the phenomenon of resident memory, herein we highlight the pleiotropic functions of CD4 tissue resident memory T cells in the lung and discuss the implications of resident memory for vaccine design.

BRD4 is a bromodomain-containing protein that binds acetylated histones to regulate transcription. In this issue of JEM, Milner et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20202512 ) show that BRD4 plays a critical role in the effector function of CD8 T cells responding to infection and cancer.

Cells constantly sense their environment, allowing the adaption of cell behavior to changing needs. Fine-tuned responses to complex inputs are computed by signaling pathways, which are wired in complex connected networks. Their activity is highly context-dependent, dynamic, and heterogeneous even between closely related individual cells. Despite lots of progress, our understanding of the precise implementation, relevance, and possible manipulation of cellular signaling in health and disease therefore remains limited. Here, we discuss the requirements, potential, and limitations of the different current technologies for the analysis of hematopoietic stem and progenitor cell signaling and its effect on cell fates.

Inflammation is an evolutionarily selected defense response to infection or tissue damage that involves activation and consumption of immune cells in order to reestablish and maintain organismal integrity. In this process, hematopoietic stem cells (HSCs) are themselves exposed to inflammatory cues and via proliferation and differentiation, replace mature immune cells in a demand-adapted fashion. Here, we review how major sources of systemic inflammation act on and subsequently shape HSC fate and function. We highlight how lifelong inflammatory exposure contributes to HSC inflamm-aging and selection of premalignant HSC clones. Finally, we explore emerging areas of interest and open questions remaining in the field.

With a growing aged population, there is an imminent need to develop new therapeutic strategies to ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation of innate immune- and inflammatory-related pathways as well as systemic inflammation have been implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. Here, we review and discuss the role of dysregulated innate immune and inflammatory signaling that contribute to the competitive advantage and clonal dominance of preleukemic and MDS-derived hematopoietic cells. We also propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities.