Annual Review of Immunology - Volume 41, 2023

I have been a scientific grasshopper throughout my career, moving from question to question within the domain of lupus. This has proven to be immensely gratifying. Scientific exploration is endlessly fascinating, and succeeding in studies you care about with colleagues and trainees leads to strong and lasting bonds. Science isn't easy; being a woman in science presents challenges, but the drive to understand a disease remains strong.

T cells and natural killer (NK) cells have complementary roles in tumor immunity, and dual T cell and NK cell attack thus offers opportunities to deepen the impact of immunotherapy. Recent work has also shown that NK cells play an important role in recruiting dendritic cells to tumors and thus enhance induction of CD8 T cell responses, while IL-2 secreted by T cells activates NK cells. Targeting of immune evasion mechanisms from the activating NKG2D receptor and its MICA and MICB ligands on tumor cells offers opportunities for therapeutic intervention. Interestingly, T cells and NK cells share several important inhibitory and activating receptors that can be targeted to enhance T cell– and NK cell–mediated immunity. These inhibitory receptor-ligand systems include CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E. We also discuss emerging therapeutic strategies based on inhibitory and activating cytokines that profoundly impact the function of both lymphocyte populations within tumors.

Immunity to infection has been extensively studied in humans and mice bearing naturally occurring or experimentally introduced germline mutations. Mouse studies are sometimes neglected by human immunologists, on the basis that mice are not humans and the infections studied are experimental and not natural. Conversely, human studies are sometimes neglected by mouse immunologists, on the basis of the uncontrolled conditions of study and small numbers of patients. However, both sides would agree that the infectious phenotypes of patients with inborn errors of immunity often differ from those of the corresponding mutant mice. Why is that? We argue that this important question is best addressed by revisiting and reinterpreting the findings of both mouse and human studies from a genetic perspective. Greater caution is required for reverse-genetics studies than for forward-genetics studies, but genetic analysis is sufficiently strong to define the studies likely to stand the test of time. Genetically robust mouse and human studies can provide invaluable complementary insights into the mechanisms of immunity to infection common and specific to these two species.

Characterization of RNA modifications has identified their distribution features and molecular functions. Dynamic changes in RNA modification on various forms of RNA are essential for the development and function of the immune system. In this review, we discuss the value of innovative RNA modification profiling technologies to uncover the function of these diverse, dynamic RNA modifications in various immune cells within healthy and diseased contexts. Further, we explore our current understanding of the mechanisms whereby aberrant RNA modifications modulate the immune milieu of the tumor microenvironment and point out outstanding research questions.

Our defenses against infection rely on the ability of the immune system to distinguish invading pathogens from self. This task is exceptionally challenging, if not seemingly impossible, in the case of retroviruses that have integrated almost seamlessly into the host. This review examines the limits of innate and adaptive immune responses elicited by endogenous retroviruses and other retroelements, the targets of immune recognition, and the consequences for host health and disease. Contrary to theoretical expectation, endogenous retroelements retain substantial immunogenicity, which manifests most profoundly when their epigenetic repression is compromised, contributing to autoinflammatory and autoimmune disease and age-related inflammation. Nevertheless, recent evidence suggests that regulated immune reactivity to endogenous retroelements is integral to immune system development and function, underpinning cancer immunosurveillance, resistance to infection, and responses to the microbiota. Elucidation of the interaction points with endogenous retroelements will therefore deepen our understanding of immune system function and contribution to disease.

The presence of granulated lymphocytes in the human uterine mucosa, known as decidua during pregnancy, or endometrium otherwise, was first noted in the nineteenth century, but it was not until 1990 that these cells were identified as a type of natural killer (NK) cell. From the outset, uterine NK (uNK) cells were found to be less cytotoxic than their circulating counterparts, peripheral NK (pNK) cells. Recently, unbiased approaches have defined three subpopulations of uNK cells, all of which cluster separately from pNK cells. Here, we review the history of research into uNK cells, including their ability to interact with placental extravillous trophoblast cells and their potential role in regulating placental implantation. We go on to review more recent advances that focus on uNK cell development and heterogeneity and their potential to defend against infection and to mediate memory effects. Finally, we consider how a better understanding of these cells could be leveraged in the future to improve outcomes of pregnancy for mothers and babies.

Modulation of the immune system is an important therapeutic strategy in a wide range of diseases, and is fundamental to the development of vaccines. However, optimally safe and effective immunotherapy requires precision in the delivery of stimulatory cues to the right cells at the right place and time, to avoid toxic overstimulation in healthy tissues or incorrect programming of the immune response. To this end, biomaterials are being developed to control the location, dose, and timing of vaccines and immunotherapies. Here we discuss fundamental concepts of how biomaterials are used to enhance immune modulation, and evidence from preclinical and clinical studies of how biomaterials-mediated immune engineering can impact the development of new therapeutics. We focus on immunological mechanisms of action and in vivo modulation of the immune system, and we also discuss challenges to be overcome to speed translation of these technologies to the clinic.

There is a dramatic remodeling of the T cell compartment during aging. The most notorious changes are the reduction of the naive T cell pool and the accumulation of memory-like T cells. Memory-like T cells in older people acquire a phenotype of terminally differentiated cells, lose the expression of costimulatory molecules, and acquire properties of senescent cells. In this review, we focus on the different subsets of age-associated T cells that accumulate during aging. These subsets include extremely cytotoxic T cells with natural killer properties, exhausted T cells with altered cytokine production, and regulatory T cells that gain proinflammatory features. Importantly, all of these subsets lose their lymph node homing capacity and migrate preferentially to nonlymphoid tissues, where they contribute to tissue deterioration and inflammaging.

The epithelial tissues that line our body, such as the skin and gut, have remarkable regenerative prowess and continually renew throughout our lifetimes. Owing to their barrier function, these tissues have also evolved sophisticated repair mechanisms to swiftly heal and limit the penetration of harmful agents following injury. Researchers now appreciate that epithelial regeneration and repair are not autonomous processes but rely on a dynamic cross talk with immunity. A wealth of clinical and experimental data point to the functional coupling of reparative and inflammatory responses as two sides of the same coin. Here we bring to the fore the immunological signals that underlie homeostatic epithelial regeneration and restitution following damage. We review our current understanding of how immune cells contribute to distinct phases of repair. When unchecked, immune-mediated repair programs are co-opted to fuel epithelial pathologies such as cancer, psoriasis, and inflammatory bowel diseases. Thus, understanding the reparative functions of immunity may advance therapeutic innovation in regenerative medicine and epithelial inflammatory diseases.

Type 2 immunity mediates protective responses to helminths and pathological responses to allergens, but it also has broad roles in the maintenance of tissue integrity, including wound repair. Type 2 cytokines are known to promote fibrosis, an overzealous repair response, but their contribution to healthy wound repair is less well understood. This review discusses the evidence that the canonical type 2 cytokines, IL-4 and IL-13, are integral to the tissue repair process through two main pathways. First, essential for the progression of effective tissue repair, IL-4 and IL-13 suppress the initial inflammatory response to injury. Second, these cytokines regulate how the extracellular matrix is modified, broken down, and rebuilt for effective repair. IL-4 and/or IL-13 amplifies multiple aspects of the tissue repair response, but many of these pathways are highly redundant and can be induced by other signals. Therefore, the exact contribution of IL-4Rα signaling remains difficult to unravel.

The evolution of IgE in mammals added an extra layer of immune protection at body surfaces to provide a rapid and local response against antigens from the environment. The IgE immune response employs potent expulsive and inflammatory forces against local antigen provocation, at the risk of damaging host tissues and causing allergic disease. Two well-known IgE receptors, the high-affinity FcεRI and low-affinity CD23, mediate the activities of IgE. Unlike other known antibody receptors, CD23 also regulates IgE expression, maintaining IgE homeostasis. This mechanism evolved by adapting the function of the complement receptor CD21. Recent insights into the dynamic character of IgE structure, its resultant capacity for allosteric modulation, and the potential for ligand-induced dissociation have revealed previously unappreciated mechanisms for regulation of IgE and IgE complexes. We describe recent research, highlighting structural studies of the IgE network of proteins to analyze the uniquely versatile activities of IgE and anti-IgE biologics.

Emerging and re-emerging respiratory viral infections pose a tremendous threat to human society, as exemplified by the ongoing COVID-19 pandemic. Upon viral invasion of the respiratory tract, the host initiates coordinated innate and adaptive immune responses to defend against the virus and to promote repair of the damaged tissue. However, dysregulated host immunity can also cause acute morbidity, hamper lung regeneration, and/or lead to chronic tissue sequelae. Here, we review our current knowledge of the immune mechanisms regulating antiviral protection, host pathogenesis, inflammation resolution, and lung regeneration following respiratory viral infections, mainly using influenza virus and SARS-CoV-2 infections as examples. We hope that this review sheds light on future research directions to elucidate the cellular and molecular cross talk regulating host recovery and to pave the way to the development of pro-repair therapeutics to augment lung regeneration following viral injury.

As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cellular damage and responds by forming the NLRP3 inflammasome, a supramolecular complex that activates caspase-1. The three major components of the NLRP3 inflammasome are NLRP3, which captures the danger signals and recruits downstream molecules; caspase-1, which elicits maturation of the cytokines IL-1β and IL-18 and processing of gasdermin D to mediate cytokine release and pyroptosis; and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which functions as a bridge connecting NLRP3 and caspase-1. In this article, we review the structural information that has been obtained on the NLRP3 inflammasome and its components or subcomplexes, with special focus on the inactive NLRP3 cage, the active NLRP3-NEK7 (NIMA-related kinase 7)-ASC inflammasome disk, and the PYD-PYD and CARD-CARD homotypic filamentous scaffolds of the inflammasome. We further implicate structure-derived mechanisms for the assembly and activation of the NLRP3 inflammasome.

Over the last decade, immunometabolism has emerged as a novel interdisciplinary field of research and yielded significant fundamental insights into the regulation of immune responses. Multiple classical approaches to interrogate immunometabolism, including bulk metabolic profiling and analysis of metabolic regulator expression, paved the way to appreciating the physiological complexity of immunometabolic regulation in vivo. Studying immunometabolism at the systems level raised the need to transition towards the next-generation technology for metabolic profiling and analysis. Spatially resolved metabolic imaging and computational algorithms for multi-modal data integration are new approaches to connecting metabolism and immunity. In this review, we discuss recent studies that highlight the complex physiological interplay between immune responses and metabolism and give an overview of technological developments that bear the promise of capturing this complexity most directly and comprehensively.

A large body of evidence generated in the last two and a half years addresses the roles of T cells in SARS-CoV-2 infection and following vaccination. Infection or vaccination induces multi-epitope CD4 and CD8 T cell responses with polyfunctionality. Early T cell responses have been associated with mild COVID-19 outcomes. In concert with animal model data, these results suggest that while antibody responses are key to prevent infection, T cell responses may also play valuable roles in reducing disease severity and controlling infection. T cell memory after vaccination is sustained for at least six months. While neutralizing antibody responses are impacted by SARS-CoV-2 variants, most CD4 and CD8 T cell responses are preserved. This review highlights the extensive progress made, and the data and knowledge gaps that remain, in our understanding of T cell responses to SARS-CoV-2 and COVID-19 vaccines.

Myeloid cells are a significant proportion of leukocytes within tissues, comprising granulocytes, monocytes, dendritic cells, and macrophages. With the identification of various myeloid cells that perform separate but complementary functions during homeostasis and disease, our understanding of tissue myeloid cells has evolved significantly. Exciting findings from transcriptomics profiling and fate-mapping mouse models have facilitated the identification of their developmental origins, maturation, and tissue-specific specializations. This review highlights the current understanding of tissue myeloid cells and the contributing factors of functional heterogeneity to better comprehend the complex and dynamic immune interactions within the healthy or inflamed tissue. Specifically, we discuss the new understanding of the contributions of granulocyte-monocyte progenitor–derived phagocytes to tissue myeloid cell heterogeneity as well as the impact of niche-specific factors on monocyte and neutrophil phenotype and function. Lastly, we explore the developing paradigm of myeloid cell heterogeneity during inflammation and disease.

Maintaining the correct number of healthy red blood cells (RBCs) is critical for proper oxygenation of tissues throughout the body. Therefore, RBC homeostasis is a tightly controlled balance between RBC production and RBC clearance, through the processes of erythropoiesis and macrophage hemophagocytosis, respectively. However, during the inflammation associated with infectious, autoimmune, or inflammatory diseases this homeostatic process is often dysregulated, leading to acute or chronic anemia. In each disease setting, multiple mechanisms typically contribute to the development of inflammatory anemia, impinging on both sides of the RBC production and RBC clearance equation. These mechanisms include both direct and indirect effects of inflammatory cytokines and innate sensing. Here, we focus on common innate and adaptive immune mechanisms that contribute to inflammatory anemias using examples from several diseases, including hemophagocytic lymphohistiocytosis/macrophage activation syndrome, severe malarial anemia during Plasmodium infection, and systemic lupus erythematosus, among others.

The complement system is an ancient collection of proteolytic cascades with well-described roles in regulation of innate and adaptive immunity. With the convergence of a revolution in complement-directed clinical therapeutics, the discovery of specific complement-associated targetable pathways in the central nervous system, and the development of integrated multi-omic technologies that have all emerged over the last 15 years, precision therapeutic targeting in Alzheimer disease and other neurodegenerative diseases and processes appears to be within reach. As a sensor of tissue distress, the complement system protects the brain from microbial challenge as well as the accumulation of dead and/or damaged molecules and cells. Additional more recently discovered diverse functions of complement make it of paramount importance to design complement-directed neurotherapeutics such that the beneficial roles in neurodevelopment, adult neural plasticity, and neuroprotective functions of the complement system are retained.

The innate immune system detects pathogens via germline-encoded receptors that bind to conserved pathogen ligands called pathogen-associated molecular patterns (PAMPs). Here we consider an additional strategy of pathogen sensing called effector-triggered immunity (ETI). ETI involves detection of pathogen-encoded virulence factors, also called effectors. Pathogens produce effectors to manipulate hosts to create a replicative niche and/or block host immunity. Unlike PAMPs, effectors are often diverse and rapidly evolving and can thus be unsuitable targets for direct detection by germline-encoded receptors. Effectors are instead often sensed indirectly via detection of their virulence activities. ETI is a viable strategy for pathogen sensing and is used across diverse phyla, including plants, but the molecular mechanisms of ETI are complex compared to simple receptor/ligand-based PAMP detection. Here we survey the mechanisms and functions of ETI, with a particular focus on emerging insights from animal studies. We suggest that many examples of ETI may remain to be discovered, hiding in plain sight throughout immunology.

Transforming growth factor β (TGF-β) is a key cytokine regulating the development, activation, proliferation, differentiation, and death of T cells. In CD4⁺ T cells, TGF-β maintains the quiescence and controls the activation of naive T cells. While inhibiting the differentiation and function of Th1 and Th2 cells, TGF-β promotes the differentiation of Th17 and Th9 cells. TGF-β is required for the induction of Foxp3 in naive T cells and the development of regulatory T cells. TGF-β is crucial in the differentiation of tissue-resident memory CD8⁺ T cells and their retention in the tissue, whereas it suppresses effector T cell function. In addition, TGF-β also regulates the generation or function of natural killer T cells, γδ T cells, innate lymphoid cells, and gut intraepithelial lymphocytes. Here I highlight the major findings and recent advances in our understanding of TGF-β regulation of T cells and provide a personal perspective of the field.