Annual review of immunology最新文献

The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.

T cell responses must be balanced to ensure adequate protection against malignant transformation and an array of pathogens while also limiting damage to healthy cells and preventing autoimmunity. T cell exhaustion serves as a regulatory mechanism to limit the activity and effector function of T cells undergoing chronic antigen stimulation. Exhausted T cells exhibit poor proliferative potential; high inhibitory receptor expression; altered transcriptome, epigenome, and metabolism; and, most importantly, reduced effector function. While exhaustion helps to restrain damage caused by aberrant T cells in settings of autoimmune disease, it also limits the ability of cells to respond against persistent infection and cancer, leading to disease progression. Here we review the process of T cell exhaustion, detailing the key characteristics and drivers as well as highlighting our current understanding of the underlying transcriptional and epigenetic programming. We also discuss how exhaustion can be targeted to enhance T cell functionality in cancer.

The choice of developing thymocytes to become CD8+ cytotoxic or CD4+ helper T cells has been intensely studied, but many of the underlying mechanisms remain to be elucidated. Recent multiomics approaches have provided much higher resolution analysis of gene expression in developing thymocytes than was previously achievable, thereby offering a fresh perspective on this question. Focusing on our recent studies using CITE-seq (cellular indexing of transcriptomes and epitopes) analyses of mouse thymocytes, we present a detailed timeline of RNA and protein expression changes during CD8 versus CD4 T cell differentiation. We also revisit our current understanding of the links between T cell receptor signaling and expression of the lineage-defining transcription factors ThPOK and RUNX3. Finally, we propose a sequential selection model to explain the tight linkage between MHC-I versus MHC-II recognition and T cell lineage choice. This model incorporates key aspects of previously proposed kinetic signaling, instructive, and stochastic/selection models.

Recent advances have contributed to a mechanistic understanding of neuroimmune interactions in the intestine and revealed an essential role of this cross talk for gut homeostasis and modulation of inflammatory and infectious intestinal diseases. In this review, we describe the innervation of the intestine by intrinsic and extrinsic neurons and then focus on the bidirectional communication between neurons and immune cells. First, we highlight the contribution of neuronal subtypes to the development of colitis and discuss the different immune and epithelial cell types that are regulated by neurons via the release of neuropeptides and neurotransmitters. Next, we review the role of intestinal inflammation in the development of visceral hypersensitivity and summarize how inflammatory mediators induce peripheral and central sensitization of gut-innervating sensory neurons. Finally, we outline the importance of immune cells and gut microbiota for the survival and function of different neuronal populations at homeostasis and during bacterial and helminth infection.

Ten-eleven translocation (TET) proteins are iron-dependent and α-ketoglutarate-dependent dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. TET proteins are recruited by transcription factors and by RNA polymerase II to modify 5mC at enhancers and gene bodies, thereby regulating gene expression during development, cell lineage specification, and cell activation. It is not yet clear, however, how the established biochemical activities of TET enzymes in oxidizing 5mC and mediating DNA demethylation relate to the known association of TET deficiency with inflammation, clonal hematopoiesis, and cancer. There are hints that the ability of TET deficiency to promote cell proliferation in a signal-dependent manner may be harnessed for cancer immunotherapy. In this review, we draw upon recent findings in cells of the immune system to illustrate established as well as emerging ideas of how TET proteins influence cellular function.

IgE-mediated food allergy (IgE-FA) occurs due to a breakdown in immune tolerance that leads to a detrimental type 2 helper T cell (T_H2) adaptive immune response. While the processes governing this loss of tolerance are incompletely understood, several host-related and environmental factors impacting the risk of IgE-FA development have been identified. Mounting evidence supports the role of an impaired epithelial barrier in the development of IgE-FA, with exposure of allergens through damaged skin and gut epithelium leading to the aberrant production of alarmins and activation of T_H2-type allergic inflammation. The treatment of IgE-FA has historically been avoidance with acute management of allergic reactions, but advances in allergen-specific immunotherapy and the development of biologics and other novel therapeutics are rapidly changing the landscape of food allergy treatment. Here, we discuss the pathogenesis and immunobiology of IgE-FA in addition to its diagnosis, prognosis, and treatment.

Environmental justice research is increasingly focused on community-engaged, participatory investigations that test interventions to improve health. Such research is primed for the use of implementation science-informed approaches to optimize the uptake and use of interventions proven to be effective. This review identifies synergies between implementation science and environmental justice with the goal of advancing both disciplines. Specifically, the article synthesizes the literature on neighborhood-, community-, and policy-level interventions in environmental health that address underlying structural determinants (e.g., structural racism) and social determinants of health. Opportunities to facilitate and scale the equitable implementation of evidence-based environmental health interventions are highlighted, using urban greening as an illustrative example. An environmental justice-focused version of the implementation science subway is provided, which highlights these principles: Remember and Reflect, Restore and Reclaim, and Reinvest. The review concludes with existing gaps and future directions to advance the science of implementation to promote environmental justice.

Food insecurity affects an estimated 691-783 million people globally and is disproportionately high in Africa and Asia. It arises from poverty, armed conflict, and climate change, among other demographic and globalization forces. This review summarizes evidence for policies and practices across five elements of the agrifood system framework and identifies gaps that inform an agenda for future research. Under availability, imbalanced agriculture policies protect primarily staple food producers, and there is limited evidence on food security impacts for smallholder and women food producers. Evidence supports the use of cash transfers and food aid for affordability and school feeding for multiple benefits. Food-based dietary guidelines can improve the nutritional quality of dietary patterns, yet they may not reflect the latest evidence or food supplies. Evidence from the newer food environment elements, promotion and sustainability, while relatively minimal, provides insight into achieving long-term impacts. To eliminate hunger, our global community should embrace integrated approaches and bring evidence-based policies and practices to scale.

Climate change poses a significant occupational health hazard. Rising temperatures and more frequent heat waves are expected to cause increasing heat-related morbidity and mortality for workers across the globe. Agricultural, construction, military, firefighting, mining, and manufacturing workers are at particularly high risk for heat-related illness (HRI). Various factors, including ambient temperatures, personal protective equipment, work arrangements, physical exertion, and work with heavy equipment may put workers at higher risk for HRI. While extreme heat will impact workers across the world, workers in low- and middle-income countries will be disproportionately affected. Tracking occupational HRI will be critical to informing prevention and mitigation strategies. Renewed investment in these strategies, including workplace heat prevention programs and regulatory standards for indoor and outdoor workers, will be needed. Additional research is needed to evaluate the effectiveness of interventions in order to successfully reduce the risk of HRI in the workplace.

Implementation science focuses on enhancing the widespread uptake of evidence-based interventions into routine practice to improve population health. However, optimizing implementation science to promote health equity in domestic and global resource-limited settings requires considering historical and sociopolitical processes (e.g., colonization, structural racism) and centering in local sociocultural and indigenous cultures and values. This review weaves together principles of decolonization and antiracism to inform critical and reflexive perspectives on partnerships that incorporate a focus on implementation science, with the goal of making progress toward global health equity. From an implementation science perspective, wesynthesize examples of public health evidence-based interventions, strategies, and outcomes applied in global settings that are promising for health equity, alongside a critical examination of partnerships, context, and frameworks operationalized in these studies. We conclude with key future directions to optimize the application of implementation science with a justice orientation to promote global health equity.