Annual review of immunology最新文献

T lymphocytes are essential for immune responses to pathogens and tumors. Their ability to rapidly clonally expand and differentiate to effector cells following infection, and then to curb effector function following infection clearance, is fundamental for adaptive immunity. Proteome remodeling in response to immune activation is a fundamental mechanism that allows T cells to swiftly reprogram for acquisition of effector function and is possible only because antigen receptor- and cytokine-driven signal transduction pathways can trigger massive increases in protein synthesis. Equally, the ability to repress protein synthesis supports a return to quiescence once pathogens are cleared to avoid autoimmunity and to generate memory T cell populations. This review discusses what is known about T cell proteomes and the regulatory mechanisms that control protein synthesis in T cells. The focus is on how this fundamental process is dynamically controlled to ensure immune homeostasis.

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved T cells that recognize microbial metabolites. They are abundant in humans and conserved during mammalian evolution, which suggests that they have important nonredundant functions. In this article, we discuss the evolutionary conservation of MAIT cells and describe their original developmental process. MAIT cells exert a wide variety of effector functions, from killing infected cells and promoting inflammation to repairing tissues. We provide insights into these functions and discuss how they result from the context of stimulation encountered by MAIT cells in different tissues and pathological settings. We describe how MAIT cell numbers and features are modified in disease states, focusing mainly on in vivo models. Lastly, we discuss emerging strategies to manipulate MAIT cells for therapeutic purposes.

The mucosal surfaces of the body are the most vulnerable points for infection because they are lined by single or multiple layers of very active epithelial cells. The main protector of these cells is the mucus system generated by the specialized goblet cell secreting its main components, the gel-forming mucins. The organization of the mucus varies from an attached mucus that is impenetrable to bacteria in the large intestine to a nonattached, more penetrable mucus in the small intestine. The respiratory tract mucus system clears particles and microorganisms from healthy lungs but causes disease if reorganized to an attached mucus that cannot be efficiently transported. Similarly, transformation of large intestine mucus from impenetrable to penetrable causes chronic inflammation directed toward the intestinal microbiota. Mucus-producing goblet cells are regulated by and responsive to signals from immune cells, and at the same time signal back to the immune system. In this review we focus on the relationship of immune cells with intestinal goblet cells and mucus, making parallels to the respiratory tract.

Immune responses are influenced by not only immune cells but also the tissue microenvironment where these cells reside. Recent advancements in understanding the underlying molecular mechanisms and structures of the epidermal tight junctions (TJs) and stratum corneum (SC) have significantly enhanced our knowledge of skin barrier functions. TJs, located in the granular layer of the epidermis, are crucial boundary elements in the differentiation process, particularly in the transition from living cells to dead cells. The SC forms from dead keratinocytes via corneoptosis and features three distinct pH zones critical for barrier function and homeostasis. Additionally, the SC-skin microbiota interactions are crucial for modulating immune responses and protecting against pathogens. In this review, we explore how these components contribute both to healthy and disease states. By targeting the skin barrier in therapeutic strategies, we can enhance its integrity, modulate immune responses, and ultimately improve outcomes for patients with inflammatory skin conditions.

The mammalian gut is a vast, diverse, and dynamic single-layer epithelial surface exposed to trillions of microbes, microbial products, and the diet. Underlying this epithelium lies the largest collection of immune cells in the body; these cells encounter luminal substances to generate antigen-specific immune responses characterized by tolerance at homeostasis and inflammation during enteric infections. How the outcomes of antigen-specific tolerance and inflammation are appropriately balanced is a central question in mucosal immunology. Furthermore, how substances large enough to generate antigen-specific responses cross the epithelium and encounter the immune system in homeostasis and during inflammation remains largely unexplored. Here we discuss the challenges presented to the gut immune system, the identified pathways by which luminal substances cross the epithelium, and insights suggesting that the pathways used by substances to cross the epithelium affect the ensuing immune response.

Communication between the nervous and immune systems is evolutionarily conserved. From primitive eukaryotes to higher mammals, neuroimmune communication utilizes multiple complex and complementary mechanisms to trigger effective but balanced responses to environmental dangers such as allergens and tissue damage. These responses result from a tight integration of the nervous and immune systems, and accumulating evidence suggests that this bidirectional communication is crucial in modulating the initiation and development of allergic inflammation. In this review, we discuss the basic mechanisms of neuroimmune communication, with a focus on the recent advances underlying the importance of such communication in the allergic immune response. We examine neuronal sensing of allergens, how neuropeptides and neurotransmitters regulate allergic immune cell functions, and how inflammatory factors derived from immune cells coordinate complex peripheral and central nervous system responses. Furthermore, we highlight how fundamental aspects of host biology, from aging to circadian rhythm, might affect these pathways. Appreciating neuroimmune communications as an evolutionarily conserved and functionally integrated system that is fundamentally involved in type 2 immunity will provide new insights into allergic inflammation and reveal exciting opportunities for the management of acute and chronic allergic diseases.

There has been an increasing effort to understand the memory responses of a complex interplay among innate, adaptive, and structural cells in peripheral organs and bone marrow. Trained immunity is coined as the de facto memory of innate immune cells and their progenitors. These cells acquire epigenetic modifications and shift their metabolism to equip an imprinted signature to a persistent fast-responsive functional state. Recent studies highlight the contribution of noncoding RNAs and modulation of chromatin structures in establishing this epigenetic readiness for potential immune perturbations. In this review, we discuss recent studies that highlight trained immunity-mediated memory responses emerging intrinsically in innate immune cells and as a complex interplay with other cells at the organ level. Lastly, we survey epigenetic contributors to trained immunity phenotypes-specifically, a recently discovered regulatory circuit coordinating the regulation of a key driver of trained immunity.

The immune system, critical for human health and implicated in many diseases, defends against pathogens, monitors physiological stress, and maintains tissue and organismal homeostasis. It exhibits substantial variability both within and across individuals and populations. Recent technological and conceptual progress in systems human immunology has provided predictive insights that link personal immune states to intervention responses and disease susceptibilities. Artificial intelligence (AI), particularly machine learning (ML), has emerged as a powerful tool for analyzing complex immune data sets, revealing hidden patterns across biological scales, and enabling predictive models for individualistic immune responses and potentially personalized interventions. This review highlights recent advances in deciphering human immune variation and predicting outcomes, particularly through the concepts of immune setpoint, immune health, and use of the immune system as a window for measuring health. We also provide a brief history of AI; review ML modeling approaches, including their applications in systems human immunology; and explore the potential of AI to develop predictive models and personal immune state embeddings to detect early signs of disease, forecast responses to interventions, and guide personalized health strategies.

Infections have imposed strong selection pressures throughout human evolution, making the study of natural selection's effects on immunity genes highly complementary to disease-focused research. This review discusses how ancient DNA studies, which have revolutionized evolutionary genetics, increase our understanding of the evolution of human immunity. These studies have shown that interbreeding between modern humans and Neanderthals or Denisovans has influenced present-day immune responses, particularly to viruses. Additionally, ancient genomics enables the tracking of how human immunity has evolved across cultural transitions, highlighting strong selection since the Bronze Age in Europe (<4,500 years) and potential genetic adaptations to epidemics raging during the Middle Ages and the European colonization of the Americas. Furthermore, ancient genomic studies suggest that the genetic risk for noninfectious immune disorders has gradually increased over millennia because alleles associated with increased risk for autoimmunity and inflammation once conferred resistance to infections. The challenge now is to extend these findings to diverse, non-European populations and to provide a more global understanding of the evolution of human immunity.

Human Immune System (HIS) mice constructed with mature human immune cells or with human hematopoietic stem cells and thymic tissue have provided an important tool for human immunological research. In this article, we first review the different types of HIS mice based on human tissues transplanted and sources of the tissues. We then focus on knowledge of human T cell development and responses obtained using HIS mouse models. These areas include the development of human T cell subsets, with a focus on αβ conventional T cells and regulatory T cells, and human T cell responses in the settings of infection, transplantation rejection and tolerance, autoimmune disease, cancer immunotherapy, and regulatory T cell therapy. We also discuss the limitations and potential future applications of HIS mouse models.