Germinal Centers.

Germinal centers (GCs) are microanatomical sites of B cell clonal expansion and antibody affinity maturation. Therein, B cells undergo the Darwinian process of somatic diversification and affinity-driven selection of immunoglobulins that produces the high-affinity antibodies essential for effective humoral immunity. Here, we review recent developments in the field of GC biology, primarily as it pertains to GCs induced by infection or immunization. First, we summarize the phenotype and function of the different cell types that compose the GC, focusing on GC B cells. Then, we review the cellular and molecular bases of affinity-dependent selection within the GC and the export of memory and plasma cells. Finally, we present an overview of the emerging field of GC clonal dynamics, focusing on how GC and post-GC selection shapes the diversity of antibodies secreted into serum.

Resistance Mechanisms to Anti-PD Cancer Immunotherapy.

The transformative success of antibodies targeting the PD-1 (programmed death 1)/B7-H1 (B7 homolog 1) pathway (anti-PD therapy) has revolutionized cancer treatment. However, only a fraction of patients with solid tumors and some hematopoietic malignancies respond to anti-PD therapy, and the reason for failure in other patients is less known. By dissecting the mechanisms underlying this resistance, current studies reveal that the tumor microenvironment is a major location for resistance to occur. Furthermore, the resistance mechanisms appear to be highly heterogeneous. Here, we discuss recent human cancer data identifying mechanisms of resistance to anti-PD therapy. We review evidence for immune-based resistance mechanisms such as loss of neoantigens, defects in antigen presentation and interferon signaling, immune inhibitory molecules, and exclusion of T cells. We also review the clinical evidence for emerging mechanisms of resistance to anti-PD therapy, such as alterations in metabolism, microbiota, and epigenetics. Finally, we discuss strategies to overcome anti-PD therapy resistance and emphasize the need to develop additional immunotherapies based on the concept of normalization cancer immunotherapy.

Spatiotemporal Adaptations of Macrophage and Dendritic Cell Development and Function.

Macrophages and conventional dendritic cells (cDCs) are distributed throughout the body, maintaining tissue homeostasis and tolerance to self and orchestrating innate and adaptive immunity against infection and cancer. As they complement each other, it is important to understand how they cooperate and the mechanisms that integrate their functions. Both are exposed to commensal microbes, pathogens, and other environmental challenges that differ widely among anatomical locations and over time. To adjust to these varying conditions, macrophages and cDCs acquire spatiotemporal adaptations (STAs) at different stages of their life cycle that determine how they respond to infection. The STAs acquired in response to previous infections can result in increased responsiveness to infection, termed training, or in reduced responses, termed paralysis, which in extreme cases can cause immunosuppression. Understanding the developmental stage and location where macrophages and cDCs acquire their STAs, and the molecular and cellular players involved in their induction, may afford opportunities to harness their beneficial outcomes and avoid or reverse their deleterious effects. Here we review our current understanding of macrophage and cDC development, life cycle, function, and STA acquisition before, during, and after infection.We propose a unified framework to explain how these two cell types adjust their activities to changing conditions over space and time to coordinate their immunosurveillance functions.

Emerging Functions of IL-33 in Homeostasis and Immunity.

Our understanding of the functions of the IL-1 superfamily cytokine and damage-associated molecular pattern IL-33 continues to evolve with our understanding of homeostasis and immunity. The early findings that IL-33 is a potent driver of type 2 immune responses promoting parasite expulsion, but also inflammatory diseases like allergy and asthma, have been further supported. Yet, as the importance of a type 2 response in tissue repair and homeostasis has emerged, so has the fundamental importance of IL-33 to these processes. In this review, we outline an evolving understanding of IL-33 immunobiology, paying particular attention to how IL-33 directs a network of ST2+ regulatory T cells, reparative and regulatory macrophages, and type 2 innate lymphoid cells that are fundamental to tissue development, homeostasis, and repair.

Decoding Cell Death: From a Veritable Library of Babel to Vade Mecum?

Programmed cell death (PCD) is a requisite feature of development and homeostasis but can also be indicative of infections, injuries, and pathologies. In concordance with these heterogeneous contexts, an array of disparate effector responses occur downstream of cell death and its clearance-spanning tissue morphogenesis, homeostatic turnover, host defense, active dampening of inflammation, and tissue repair. This raises a fundamental question of how a single contextually appropriate response ensues after an event of PCD. To explore how complex inputs may together tailor the specificity of the resulting effector response, here we consider (a) the varying contexts during which different cell death modalities are observed, (b) the nature of the information that can be passed on by cell corpses, and (c) the ways by which efferocyte populations synthesize signals from dying cells with those from the surrounding microenvironment.

Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies.

The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Researchers using eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit.

Primary Atopic Disorders.

Primary atopic disorders describes a series of monogenic diseases that have allergy- or atopic effector-related symptoms as a substantial feature. The underlying pathogenic genetic lesions help illustrate fundamental pathways in atopy, opening up diagnostic and therapeutic options for further study in those patients, but ultimately for common allergic diseases as well. Key pathways affected in these disorders include T cell receptor and B cell receptor signaling, cytokine signaling, skin barrier function, and mast cell function, as well as pathways that have not yet been elucidated. While comorbidities such as classically syndromic presentation or immune deficiency are often present, in some cases allergy alone is the presenting symptom, suggesting that commonly encountered allergic diseases exist on a spectrum of monogenic and complex genetic etiologies that are impacted by environmental risk factors.

Neonatal T Cells: A Reinterpretation.

Neonatal CD4+ and CD8+ T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.

Microbiota Metabolites in Health and Disease.

Metabolism is one of the strongest drivers of interkingdom interactions-including those between microorganisms and their multicellular hosts. Traditionally thought to fuel energy requirements and provide building blocks for biosynthetic pathways, metabolism is now appreciated for its role in providing metabolites, small-molecule intermediates generated from metabolic processes, to perform various regulatory functions to mediate symbiotic relationships between microbes and their hosts. Here, we review recent advances in our mechanistic understanding of how microbiota-derived metabolites orchestrate and support physiological responses in the host, including immunity, inflammation, defense against infections, and metabolism. Understanding how microbes metabolically communicate with their hosts will provide us an opportunity to better describe how a host interacts with all microbes-beneficial, pathogenic, and commensal-and an opportunity to discover new ways to treat microbial-driven diseases.

Evolution of Alternative Adaptive Immune Systems in Vertebrates.

Adaptive immunity in jawless fishes is based on antigen recognition by three types of variable lymphocyte receptors (VLRs) composed of variable leucine-rich repeats, which are differentially expressed by two T-like lymphocyte lineages and one B-like lymphocyte lineage. The T-like cells express either VLRAs or VLRCs of yet undefined antigen specificity, whereas the VLRB antibodies secreted by B-like cells bind proteinaceous and carbohydrate antigens. The incomplete VLR germline genes are assembled into functional units by a gene conversion-like mechanism that employs flanking variable leucine-rich repeat sequences as templates in association with lineage-specific expression of cytidine deaminases. B-like cells develop in the hematopoietic typhlosole and kidneys, whereas T-like cells develop in the thymoid, a thymus-equivalent region at the gill fold tips. Thus, the dichotomy between T-like and B-like cells and the presence of dedicated lymphopoietic tissues emerge as ancestral vertebrate features, whereas the somatic diversification of structurally distinct antigen receptor genes evolved independently in jawless and jawed vertebrates.

Molecular Machines that Facilitate Bacterial Outer Membrane Protein Biogenesis.

Almost all outer membrane proteins (OMPs) in Gram-negative bacteria contain a ß-barrel domain that spans the outer membrane (OM). To reach the OM, OMPs must be translocated across the inner membrane by the Sec machinery, transported across the crowded periplasmic space through the assistance of molecular chaperones, and finally assembled (folded and inserted into the OM) by the ß-barrel assembly machine. In this review, we discuss how considerable new insights into the contributions of these factors to OMP biogenesis have emerged in recent years through the development of novel experimental, computational, and predictive methods. In addition, we describe recent evidence that molecular machines that were thought to function independently might interact to form dynamic intermembrane supercomplexes. Finally, we discuss new results that suggest that OMPs are inserted primarily near the middle of the cell and packed into supramolecular structures (OMP islands) that are distributed throughout the OM.

Triumphs and Challenges of Natural Product Discovery in the Postgenomic Era.

Natural products have played significant roles as medicine and food throughout human history. Here, we first provide a brief historical overview of natural products, their classification and biosynthetic origins, and the microbiological and genetic methods used for their discovery. We also describe and discuss the technologies that revolutionized the field, which transitioned from classic genetics to genome-centric discovery approximately two decades ago. We then highlight the most recent advancements and approaches in the current postgenomic era, in which genome mining is a standard operation and high-throughput analytical methods allow parallel discovery of genes and molecules at an unprecedented pace. Finally, we discuss the new challenges faced by the field of natural products and the future of systematic heterologous expression and strain-independent discovery, which promises to deliver more molecules in vials than ever before.

The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules.

To monitor the health of cells, the immune system tasks antigen-presenting cells with gathering antigens from other cells and bringing them to CD8 T cells in the form of peptides bound to MHC-I molecules. Most cells would be unable to perform this function because they use their MHC-I molecules to exclusively present peptides derived from the cell's own proteins. However, the immune system evolved mechanisms for dendritic cells and some other phagocytes to sample and present antigens from the extracellular milieu on MHC-I through a process called cross-presentation. How this important task is accomplished, its role in health and disease, and its potential for exploitation are the subject of this review.

Deep learning meets histones at the replication fork.

Epigenetic inheritance of heterochromatin requires transfer of parental H3-H4 tetramers to both daughter duplexes during replication. Three recent papers exploit yeast genetics coupled to inheritance assays and AlphaFold2-multimer predictions coupled to biochemistry to reveal that a replisome component (Mrc1/CLASPIN) is an H3-H4 tetramer chaperone important for parental histone transfer to daughters.

Virology-The next fifty years.

Virology has made enormous advances in the last 50 years but has never faced such scrutiny as it does today. Herein, we outline some of the major advances made in virology during this period, particularly in light of the COVID-19 pandemic, and suggest some areas that may be of research importance in the next 50 years. We focus on several linked themes: cataloging the genomic and phenotypic diversity of the virosphere; understanding disease emergence; future directions in viral disease therapies, vaccines, and interventions; host-virus interactions; the role of viruses in chronic diseases; and viruses as tools for cell biology. We highlight the challenges that virology will face moving forward-not just the scientific and technical but also the social and political. Although there are inherent limitations in trying to outline the virology of the future, we hope this article will help inspire the next generation of virologists.

Proteomics: A new dimension to decode small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant malignancy. Conquering it will require deep insight into its biology. In this issue of Cell, Liu and colleagues describe proteomic and phosphoproteomic landscapes of resected SCLC tumors and illustrate the potential of this knowledge to identify new SCLC vulnerabilities.

Transforming obesity: The advancement of multi-receptor drugs.

For more than a century, physicians have searched for ways to pharmacologically reduce excess body fat. The tide has finally turned with recent advances in biochemically engineered agonists for the receptor of glucagon-like peptide-1 (GLP-1) and their use in GLP-1-based polyagonists. These polyagonists reduce body weight through complementary pharmacology by incorporating the receptors for glucagon and/or the glucose-dependent insulinotropic polypeptide (GIP). In their most advanced forms, gut-hormone polyagonists achieve an unprecedented weight reduction of up to ∼20%-30%, offering a pharmacological alternative to bariatric surgery. Along with favorable effects on glycemia, fatty liver, and kidney disease, they also offer beneficial effects on the cardiovascular system and adipose tissue. These new interventions, therefore, hold great promise for the future of anti-obesity medications.

Focus on fungi.

Fungi play critical roles in the homeostasis of ecosystems globally and have emerged as significant causes of an expanding repertoire of devastating diseases in plants, animals, and humans. In this Commentary, we highlight the importance of fungal pathogens and argue for concerted research efforts to enhance understanding of fungal virulence, antifungal immunity, novel drug targets, antifungal resistance, and the mycobiota to improve human health.

Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas.

Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.

The plant immune system: From discovery to deployment.

Plant diseases cause famines, drive human migration, and present challenges to agricultural sustainability as pathogen ranges shift under climate change. Plant breeders discovered Mendelian genetic loci conferring disease resistance to specific pathogen isolates over 100 years ago. Subsequent breeding for disease resistance underpins modern agriculture and, along with the emergence and focus on model plants for genetics and genomics research, has provided rich resources for molecular biological exploration over the last 50 years. These studies led to the identification of extracellular and intracellular receptors that convert recognition of extracellular microbe-encoded molecular patterns or intracellular pathogen-delivered virulence effectors into defense activation. These receptor systems, and downstream responses, define plant immune systems that have evolved since the migration of plants to land ∼500 million years ago. Our current understanding of plant immune systems provides the platform for development of rational resistance enhancement to control the many diseases that continue to plague crop production.