Annual Review of Immunology - Volume 39, 2021

An imbalance in the microbiota may contribute to many human illnesses, which has prompted efforts to rebalance it by targeting the microbes themselves. However, by supplying the habitat, the host wields a prominent influence over microbial growth at body surfaces, raising the possibility that rebalancing the microbiota by targeting our immune system would be a viable alternative. Host control mechanisms that sculpt the microbial habitat form a functional unit with the microbiota, termed microbiota-nourishing immunity, that confers colonization resistance against pathogens. The host components of microbiota-nourishing immunity can be viewed as habitat filters that select for microbial traits licensing growth and survival in host habitat patches. Here we review current knowledge of how host-derived habitat filters shape the size, species composition, and spatial heterogeneity of the microbiota and discuss whether these host control mechanisms could be harnessed for developing approaches to rebalance microbial communities during dysbiosis.

Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens and greater availability of allograft sources, transplant recipients still endure the morbidity and mortality of graft-versus-host disease (GVHD). Herein, we identify key aspects of acute and chronic GVHD pathophysiology, including host/donor cell effectors, gut dysbiosis, immune system and cytokine imbalance, and the interface between inflammation and tissue fibrosis. In particular, we also summarize the translational application of this heightened understanding of immune dysregulation in the design of novel therapies to prevent and treat GVHD.

T lymphocytes, the major effector cells in cellular immunity, produce cytokines in immune responses to mediate inflammation and regulate other types of immune cells. Work in the last three decades has revealed significant heterogeneity in CD4⁺ T cells, in terms of their cytokine expression, leading to the discoveries of T helper 1 (Th1), Th2, Th17, and T follicular helper (Tfh) cell subsets. These cells possess unique developmental and regulatory pathways and play distinct roles in immunity and immune-mediated pathologies. Other types of T cells, including regulatory T cells and γδ T cells, as well as innate lymphocytes, display similar features of subpopulations, which may play differential roles in immunity. Mechanisms exist to prevent cytokine production by T cells to maintain immune tolerance to self-antigens, some of which may also underscore immune exhaustion in the context of tumors. Understanding cytokine regulation and function has offered innovative treatment of many human diseases.

Nearly all animal cells contain proteins evolved to trigger the destruction of the cell in which they reside. The activation of these proteins occurs via sequential programs, and much effort has been expended in delineating the molecular mechanisms underlying the resulting processes of programmed cell death (PCD). These efforts have led to the definition of apoptosis as a form of nonimmunogenic PCD that is required for normal development and tissue homeostasis, and of pyroptosis and necroptosis as forms of PCD initiated by pathogen infection that are associated with inflammation and immune activation. While this paradigm has served the field well, numerous recent studies have highlighted cross talk between these programs, challenging the idea that apoptosis, pyroptosis, and necroptosis are linear pathways with defined immunological outputs. Here, we discuss the emerging idea of cell death as a signaling network, considering connections between cell death pathways both as we observe them now and in their evolutionary origins. We also discuss the engagement and subversion of cell death pathways by pathogens, as well as the key immunological outcomes of these processes.

B cell subsets differ in development, tissue distribution, and mechanisms of activation. In response to infections, however, all can differentiate into extrafollicular plasmablasts that rapidly provide highly protective antibodies, indicating that these plasmablasts are the main humoral immune response effectors. Yet, the effectiveness of this response type depends on the presence of antigen-specific precursors in the circulating mature B cell pool, a pool that is generated initially through the stochastic processes of B cell receptor assembly. Importantly, germinal centers then mold the repertoire of this B cell pool to be increasingly responsive to pathogens by generating a broad array of antimicrobial memory B cells that act as highly effective precursors of extrafollicular plasmablasts. Such B cell repertoire molding occurs in two ways: continuously via the chronic germinal centers of mucosal lymphoid tissues, driven by the presence of the microbiome, and via de novo generated germinal centers following acute infections. For effectively evaluating humoral immunity as a correlate of immune protection, it might be critical to measure memory B cell pools in addition to antibody titers.

Dendritic cells (DCs) possess the ability to integrate information about their environment and communicate it to other leukocytes, shaping adaptive and innate immunity. Over the years, a variety of cell types have been called DCs on the basis of phenotypic and functional attributes. Here, we refocus attention on conventional DCs (cDCs), a discrete cell lineage by ontogenetic and gene expression criteria that best corresponds to the cells originally described in the 1970s. We summarize current knowledge of mouse and human cDC subsets and describe their hematopoietic development and their phenotypic and functional attributes. We hope that our effort to review the basic features of cDC biology and distinguish cDCs from related cell types brings to the fore the remarkable properties of this cell type while shedding some light on the seemingly inordinate complexity of the DC field.

Type 2 immunity helps protect the host from infection, but it also plays key roles in tissue homeostasis, metabolism, and repair. Unfortunately, inappropriate type 2 immune reactions may lead to allergy and asthma. Group 2 innate lymphoid cells (ILC2s) in the lungs respond rapidly to local environmental cues, such as the release of epithelium-derived type 2 initiator cytokines/alarmins, producing type 2 effector cytokines such as IL-4, IL-5, and IL-13 in response to tissue damage and infection. ILC2s are associated with the severity of allergic asthma, and experimental models of lung inflammation have shown how they act as playmakers, receiving signals variously from stromal and immune cells as well as the nervous system and then distributing cytokine cues to elicit type 2 immune effector functions and potentiate CD4⁺ T helper cell activation, both of which characterize the pathology of allergic asthma. Recent breakthroughs identifying stromal- and neuronal-derived microenvironmental cues that regulate ILC2s, along with studies recognizing the potential plasticity of ILC2s, have improved our understanding of the immunoregulation of asthma and opened new avenues for drug discovery.

Multiple sclerosis (MS) is a chronic disease that is characterized by the inappropriate invasion of lymphocytes and monocytes into the central nervous system (CNS), where they orchestrate the demyelination of axons, leading to physical and cognitive disability. There are many reasons immunologists should be interested in MS. Aside from the fact that there is still significant unmet need for patients living with the progressive form of the disease, MS is a case study for how immune cells cross CNS barriers and subsequently interact with specialized tissue parenchymal cells. In this review, we describe the types of immune cells that infiltrate the CNS and then describe interactions between immune cells and glial cells in different types of lesions. Lastly, we provide evidence for CNS-compartmentalized immune cells and speculate on how this impacts disease progression for MS patients.

Primary immunodeficiency diseases (PIDs) are a rapidly growing, heterogeneous group of genetically determined diseases characterized by defects in the immune system. While individually rare, collectively PIDs affect between 1/1,000 and 1/5,000 people worldwide. The clinical manifestations of PIDs vary from susceptibility to infections to autoimmunity and bone marrow failure. Our understanding of the human immune response has advanced by investigation and discovery of genetic mechanisms of PIDs. Studying patients with isolated genetic variants in proteins that participate in complex signaling pathways has led to an enhanced understanding of host response to infection, and mechanisms of autoimmunity and autoinflammation. Identifying genetic mechanisms of PIDs not only furthers immunological knowledge but also benefits patients by dictating targeted therapies or hematopoietic stem cell transplantation. Here, we highlight several of these areas in the field of primary immunodeficiency, with a focus on the most recent advances.

The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.

The innate immune response is a rapid response to pathogens or danger signals. It is precisely activated not only to efficiently eliminate pathogens but also to avoid excessive inflammation and tissue damage. cis-Regulatory element–associated chromatin architecture shaped by epigenetic factors, which we define as the epiregulome, endows innate immune cells with specialized phenotypes and unique functions by establishing cell-specific gene expression patterns, and it also contributes to resolution of the inflammatory response. In this review, we focus on two aspects: (a) how niche signals during lineage commitment or following infection and pathogenic stress program epiregulomes by regulating gene expression levels, enzymatic activities, or gene-specific targeting of chromatin modifiers and (b) how the programed epiregulomes in turn mediate regulation of gene-specific expression, which contributes to controlling the development of innate cells, or the response to infection and inflammation, in a timely manner. We also discuss the effects of innate immunometabolic rewiring on epiregulomes and speculate on several future challenges to be encountered during the exploration of the master regulators of epiregulomes in innate immunity and inflammation.

Tissue-resident macrophages are present in most tissues with developmental, self-renewal, or functional attributes that do not easily fit into a textbook picture of a plastic and multifunctional macrophage originating from hematopoietic stem cells; nor does it fit a pro- versus anti-inflammatory paradigm. This review presents and discusses current knowledge on the developmental biology of macrophages from an evolutionary perspective focused on the function of macrophages, which may aid in study of developmental, inflammatory, tumoral, and degenerative diseases. We also propose a framework to investigate the functions of macrophages in vivo and discuss how inherited germline and somatic mutations may contribute to the roles of macrophages in diseases.

For many infections and almost all vaccines, neutralizing-antibody-mediated immunity is the primary basis and best functional correlate of immunological protection. Durable long-term humoral immunity is mediated by antibodies secreted by plasma cells that preexist subsequent exposures and by memory B cells that rapidly respond to infections once they have occurred. In the midst of the current pandemic of coronavirus disease 2019, it is important to define our current understanding of the unique roles of memory B cells and plasma cells in immunity and the factors that control the formation and persistence of these cell types. This fundamental knowledge is the basis to interpret findings from natural infections and vaccines. Here, we review transcriptional and metabolic programs that promote and support B cell fates and functions, suggesting points at which these pathways do and do not intersect.

Classically, skin was considered a mere structural barrier protecting organisms from a diversity of environmental insults. In recent decades, the cutaneous immune system has become recognized as a complex immunologic barrier involved in both antimicrobial immunity and homeostatic processes like wound healing. To sense a variety of chemical, mechanical, and thermal stimuli, the skin harbors one of the most sophisticated sensory networks in the body. However, recent studies suggest that the cutaneous nervous system is highly integrated with the immune system to encode specific sensations into evolutionarily conserved protective behaviors. In addition to directly sensing pathogens, neurons employ novel neuroimmune mechanisms to provide host immunity. Therefore, given that sensation underlies various physiologies through increasingly complex reflex arcs, a much more dynamic picture is emerging of the skin as a truly systemic organ with highly coordinated physical, immunologic, and neural functions in barrier immunology.

Recent evidence supports the notion that mitochondrial metabolism is necessary for T cell activation, proliferation, and function. Mitochondrial metabolism supports T cell anabolism by providing key metabolites for macromolecule synthesis and generating metabolites for T cell function. In this review, we focus on how mitochondrial metabolism controls conventional and regulatory T cell fates and function.

Natural killer (NK) cells are innate lymphocytes that provide critical host defense against pathogens and cancer. Originally heralded for their early and rapid effector activity, NK cells have been recognized over the last decade for their ability to undergo adaptive immune processes, including antigen-driven clonal expansion and generation of long-lived memory. This review presents an overview of how NK cells lithely partake in both innate and adaptive responses and how this versatility is manifest in human NK cell–mediated immunity.

The immune system has coevolved with extensive microbial communities living on barrier sites that are collectively known as the microbiota. It is increasingly clear that microbial antigens and metabolites engage in a constant dialogue with the immune system, leading to microbiota-specific immune responses that occur in the absence of inflammation. This form of homeostatic immunity encompasses many arms of immunity, including B cell responses, innate-like T cells, and conventional T helper and T regulatory responses. In this review we summarize known examples of innate-like T cell and adaptive immunity to the microbiota, focusing on fundamental aspects of commensal immune recognition across different barrier sites. Furthermore, we explore how this cross talk is established during development, emphasizing critical temporal windows that establish long-term immune function. Finally, we highlight how dysregulation of immunity to the microbiota can lead to inflammation and disease, and we pinpoint outstanding questions and controversies regarding immune system–microbiota interactions.

Posttranscriptional control of mRNA regulates various biological processes, including inflammatory and immune responses. RNA-binding proteins (RBPs) bind cis-regulatory elements in the 3′ untranslated regions (UTRs) of mRNA and regulate mRNA turnover and translation. In particular, eight RBPs (TTP, AUF1, KSRP, TIA-1/TIAR, Roquin, Regnase, HuR, and Arid5a) have been extensively studied and are key posttranscriptional regulators of inflammation and immune responses. These RBPs sometimes collaboratively or competitively bind the same target mRNA to enhance or dampen regulatory activities. These RBPs can also bind their own 3′ UTRs to negatively or positively regulate their expression. Both upstream signaling pathways and microRNA regulation shape the interactions between RBPs and target RNA. Dysregulation of RBPs results in chronic inflammation and autoimmunity. Here, we summarize the functional roles of these eight RBPs in immunity and their associated diseases.

The surfaces of all living organisms and most secreted proteins share a common feature: They are glycosylated. As the outermost-facing molecules, glycans participate in nearly all immunological processes, including driving host-pathogen interactions, immunological recognition and activation, and differentiation between self and nonself through a complex array of pathways and mechanisms. These fundamental immunologic roles are further cast into sharp relief in inflammatory, autoimmune, and cancer disease states in which immune regulation goes awry. Here, we review the broad impact of glycans on the immune system and discuss the changes and clinical opportunities associated with the onset of immunologic disease.