Annual review of immunology最新文献

Throughout biology, the pursuit of genotype-phenotype relationships has provided foundational knowledge upon which new concepts and hypotheses are built. Genetic perturbation, whether occurring naturally or in experimental settings, is the mainstay of mechanistic dissection in biological systems. The unbiased discovery of causal genetic lesions via forward genetics in patients who have a rare disease elucidates a particularly impactful set of genotype-phenotype relationships. Here, we review the field of genetic errors of immunity, often termed inborn errors of immunity (IEIs), in a framework aimed at highlighting the powerful real-world immunology insights provided collectively and individually by these (approximately) 500 disorders. By conceptualizing essential immune functions in a model of the adaptive arsenal of rapid defenses, we organize IEIs based on immune circuits in which sensors, relays, and executioners cooperate to carry out pathogen clearance functions in an effective yet regulated manner. We review and discuss findings from IEIs that not only reinforce known immunology concepts but also offer surprising phenotypes, prompting an opportunity to refine our understanding of immune system function.

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.

Initially discovered for its role mediating the deleterious effects of environmental contaminants, the aryl hydrocarbon receptor (AHR) is now known to be a crucial regulator of the immune system. The expanding list of AHR ligands includes synthetic and naturally derived molecules spanning pollutants, phytochemicals, pharmaceuticals, and substances derived from amino acids and microorganisms. The consequences of engaging AHR vary, depending on factors such as the AHR ligand, cell type, immune challenge, developmental state, dose, and timing of exposure relative to the immune stimulus. This review frames this complexity using the recently identified key characteristics of agents that affect immune system function (altered cell signaling, proliferation, differentiation, effector function, communication, trafficking, death, antigen presentation and processing, and tolerance). The use of these key characteristics provides a scaffold for continued discovery of how AHR and its myriad ligands influence the immune system, which will help harness the power of this enigmatic receptor to prevent or treat disease.

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 cells 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 and airways. 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.

Prosurvival tumor necrosis factor receptor (TNFR) superfamily (TNFRSF) members on T cells, including 4-1BB, CD27, GITR, and OX40, support T cell accumulation during clonal expansion, contributing to T cell memory. During viral infection, tumor necrosis factor superfamily (TNFSF) members on inflammatory monocyte-derived antigen-presenting cells (APCs) provide a postpriming signal (signal 4) for T cell accumulation, particularly in the tissues. Patients with loss-of-function mutations in TNFR/TNFSF members reveal a critical role for 4-1BB and CD27 in CD8 T cell control of Epstein-Barr virus and other childhood infections and of OX40 in CD4 T cell responses. Here, on the 20th anniversary of a previous Annual Review of Immunology article about TNFRSF signaling in T cells, we discuss the effects of endogenous TNFRSF signals in T cells upon recognition of TNFSF members on APCs; the role of TNFRSF members, including TNFR2, on regulatory T cells; and recent advances in the incorporation of TNFRSF signaling in T cells into immunotherapeutic strategies for cancer.

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 $upalpha$$upbeta$ 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.

The persistence of SARS-CoV-2 infections at a global level reflects the repeated emergence of variant strains encoding unique constellations of mutations. These variants have been generated principally because of a dynamic host immune landscape, the countermeasures deployed to combat disease, and selection for enhanced infection of the upper airway and respiratory transmission. The resulting viral diversity creates a challenge for vaccination efforts to maintain efficacy, especially regarding humoral aspects of protection. Here, we review our understanding of how SARS-CoV-2 has evolved during the pandemic, the immune mechanisms that confer protection, and the impact viral evolution has had on transmissibility and adaptive immunity elicited by natural infection and/or vaccination. Evidence suggests that SARS-CoV-2 evolution initially selected variants with increased transmissibility but currently is driven by immune escape. The virus likely will continue to drift to maintain fitness until countermeasures capable of disrupting transmission cycles become widely available.

I have spent more than the last 40 years at the University of California, San Francisco (UCSF), studying T cell receptor (TCR) signaling. I was blessed with supportive mentors, an exceptionally talented group of trainees, and wonderful collaborators and colleagues during my journey who have enabled me to make significant contributions to our understanding of how the TCR initiates signaling. TCR signaling events contribute to T cell development as well as to mature T cell activation and differentiation.

Barrier tissues are highly innervated by sensory and autonomic nerves that are positioned in close proximity to both stromal and immune cell populations. Together with a growing awareness of the far-reaching consequences of neuroimmune interactions, recent studies have uncovered key mechanisms through which they contribute to organ homeostasis and immunity. It has also become clear that dysregulation of such interactions is implicated in the development of chronic lung diseases. This review describes the characteristics of the lung nervous system and discusses the molecular mechanisms that underlie lung neuroimmune interactions in infection and disease. We have contextualized the current literature and identified opportune areas for further investigation. Indeed, both the lung-brain axis and local neuroimmune interactions hold enormous potential for the exploration and development of novel therapeutic strategies targeting lung diseases.