Type 2 immune responses play a crucial role in host defense against parasitic infections but can also promote the development of allergies and asthma. This response is orchestrated primarily by group 2 innate lymphoid cells (ILC2) and helper type 2 (Th2) cells, both of which undergo substantial metabolic reprogramming as they transition from resting to activated states. Understanding these metabolic adaptations not only provides insights into the fundamental biology of ILC2 and Th2 cells but also opens up potential therapeutic avenues for the identification of novel metabolic targets that can extend the current treatment regimens for diseases in which type 2 immune responses play pivotal roles. By integrating recent findings, this review underscores the significance of cellular metabolism in orchestrating immune functions and highlights future directions for research in this evolving field.

Allergic diseases are acute and chronic inflammatory conditions resulting from disproportionate responses to environmental stimuli. Affecting approximately 40% of the global population, these diseases significantly contribute to morbidity and increasing health care costs. Allergic reactions are triggered by pollen, house dust mites, animal dander, mold, food antigens, venoms, toxins, and drugs. This review explores the pivotal role of the epithelium in the skin, lungs, and gastrointestinal tract in regulating the allergic response and delves into the mechanisms of tissue-specific epithelial-immune interactions in this context, with recent advances highlighting their roles in the initiation, elicitation, and resolution phases of allergy. Understanding these intricate interactions at epithelial barriers is essential for developing targeted therapies to manage and treat allergic diseases.

Much is known about the importance of macrophages for regulating diverse aspects of organismal physiology, alongside their essential roles in inflammation. Relatively unexplored are the processes influencing macrophages' and monocytes' ability to invade into the tissues where they carry out these functions. Drosophila plasmatocytes, also called hemocytes, show similarities to vertebrate macrophages in their function and their molecular specification; they have recently been shown to also infiltrate into tissues during development and inflammation. Extravasation across vasculature, into tumors, the brain, and adipose tissue have all been observed. We discuss the striking parallels in some of these systems to vertebrate immune responses, including a requirement for tumor necrosis factor. Finally, we highlight the new pathways regulating infiltration found in the fly that remain as yet unexamined in a vertebrate context.

The presence of B cells and their subtypes in the tumor environment has been recognized a for very long time. Immunoglobulins specific for more than thousands of tumor-associated antigens were detected in the sera of patients with cancer; however, antibody-mediated cancer cell killing is usually impaired. The role of humoral immune response remained elusive until recently, with new discoveries regarding their contribution in regulating antitumor immunity, particularly during immunotherapy. Humoral immunity has been described to promote or attenuate tumorigenesis and can have opposing effects on therapeutic outcome in different tumor entities. The antagonism effect of B cells depends on their subtypes and immunoglobulin isotypes and is regulated by their spatial distribution and localization. In this short review, we will focus on how the spatial organization of B cells within the tumor microenvironment, tumor-associated lymph nodes, and tertiary lymphoid structures define their fate and function and contribute to the regulation of antitumor immunity.

Allergies are among the top causes of chronic disease in children. Their pathogenesis classically involves T helper 2 (Th2)-type inflammation driven by IgE-mediated allergen sensing. Triggers influencing allergic disease occur early in life, including before birth. The immature fetal immune system and mucosal barriers undergo periods of plasticity that are open to longitudinal programming by maternal influence. Evidence supports the importance of the maternal immune system in shaping perinatal immunity, as the transfer of cytokines, antibodies, and cells promotes offspring protection from pathogens. However, the same components may lead to allergic predisposition. Maternal-fetal interactions are further modified by epigenetic, metabolic, dietary, and microbiome-mediated effects. Here, we review how diverse maternal exposures and mediators signal across the placenta and through nursing perinatally to promote future tolerance or enhance reactivity against allergens. Improved understanding of the mechanisms predisposing for allergic disease in early life can guide the development of new therapeutics and preventative lifestyle modifications.

Tumor-associated macrophages (TAMs) constitute the primary subset of immune cells within the tumor microenvironment (TME). Exhibiting both phenotypic and functional heterogeneity, TAMs play distinct roles in tumor initiation, progression, and responses to therapy in patients with cancer. In response to various immune and metabolic cues within the TME, TAMs dynamically alter their metabolic profiles to adapt. Changes in glucose, amino acid, and lipid metabolism in TAMs, as well as their interaction with oncometabolites, not only sustain their energy demands but also influence their impact on tumor immune responses. Understanding the molecular mechanisms underlying the metabolic reprogramming of TAMs and their orchestration of metabolic processes can offer insights for the development of novel cancer immunotherapies targeting TAMs. Here, we discuss how metabolism reprograms macrophages in the TME and review clinical trials aiming to normalize metabolic alterations in TAMs and alleviate TAM-mediated immune suppression and protumor activity.

Successful treatment of infectious diseases requires a multiprong approach involving strategies that limit pathogen burdens and that limit disease. Traditionally, disease defense is thought to be a direct function of pathogen killing, and thus, our current methods for treating infections have largely relied on pathogen eradication, leading to drug resistance. Strategies that target the virulence of the pathogen, called antivirulence, have been proposed to be a necessary strategy to integrate into our infectious disease toolbox to promote disease defense and alleviate the burden of drug resistance. Traditional antivirulence strategies have largely focused on developing compounds that directly target microbial virulence factors or products to impair their ability to initiate and sustain infection. As virulence is linked to pathogen fitness, simply targeting a virulence factor may not be sufficient to overcome the ability of pathogens evolving resistance. In this review, I discuss co-operative defenses that hosts have evolved to promote antivirulence mechanisms that suppress pathogen virulence without having a negative impact on pathogen fitness. I also discuss the different definitions antivirulence has been assigned over the years and suggest a more holistic one. Co-operative defenses remain an underexplored resource in medicine, and by learning from how hosts have evolved to promote antivirulence, we have the potential to develop disease defense interventions without the risk of pathogens developing drug resistance.

Aging is one of the greatest risk factors for several chronic diseases and is accompanied by a progressive decline of cellular and organ function. Recent studies have highlighted the changes in metabolism as one of the main drivers of organism dysfunctions during aging and how that strongly deteriorate immune cell performance and function. Indeed, a dysfunctional immune system has been shown to have a pleiotropic impact on the organism, accelerating the overall aging process of an individual. Intrinsic and extrinsic factors are responsible for such metabolic alterations. Understanding the contribution, regulation, and connection of these different factors is fundamental to comprehend the process of aging and develop approaches to mitigate age-related immune decline. Here, we describe metabolic perturbations occurring at cellular and systemic levels. Particularly, we emphasize the interplay between metabolism and immunosenescence and describe novel interventions to protect immune function and promote health span.

Allergic diseases continue to increase in prevalence across the globe. Decades of research has uncovered the cytokines and transcription factors that are central to the allergic immune response, but only in the last few years have we begun to understand the metabolic requirements of allergic immunity. Here, we discuss the metabolic features of so-called 'type 2' lymphocytes, which are heavily implicated in allergy. We highlight the central role that nuclear receptors, such as peroxisome proliferator-activated receptor gamma, play in type 2 lymphocyte biology and explore the influence of dietary and microbial factors in allergic inflammation. In the future, targeting metabolic checkpoints may offer a meaningful way of treating patients with allergic disorders.

As cancer immunotherapy evolves, tissue-resident memory (T) cells remain key contributors to the antitumoral immune response due to their ability to mediate local tumor control, high expression of immune checkpoints, potential to respond to immunotherapy, and location across tissue sites where distal tumor metastases occur. This review synthesizes recent findings on the biology of T cells, their role in cancer, and their interactions with the tumor microenvironment. We also identify several critical research gaps, such as how mechanistic interrogation of T cell function is required for integration into therapeutics, proposing a focused research agenda to better exploit their potential.

Neutrophils, the first responders of the innate immune system, can turn on a range of effector functions upon activation. Emerging research shows activated neutrophils undergo highly dynamic metabolic rewiring. This metabolic rewiring provides energy and reducing power to fuel effector functions and modulate signaling molecules to regulate neutrophil functions. Here, we review the current understanding of the specific metabolic requirements and regulators of neutrophil migration, neutrophil extracellular traps release, and pathogen killing. Particularly, we discuss how major carbohydrate metabolic pathways, including glycolysis, glycogen cycling, pentose phosphate pathway, and TCA cycle, are rewired upon neutrophil activation to support these functions. Continued investigation into the metabolic regulators of neutrophil functions can lead to therapeutic opportunities in various diseases.

Intricate immune regulation is required at mucosal surfaces to allow tolerance to microbiota and harmless allergens and to prevent overexuberant inflammatory responses to pathogens. The cytokine Interleukin-10 (IL-10) is a key mediator of mucosal immune regulation. While IL-10 can be produced by virtually all cells of the immune system, many of its in vivo functions depend upon its production by regulatory or effector T cell populations and its signalling to macrophages, dendritic cells and specific T cell subsets. In this review, we discuss our current understanding of the role of IL-10 in regulation of immune responses, with a focus on its context-specific roles in intestinal homeostasis, respiratory infection and asthma. We highlight the importance of appropriate production and function of IL-10 for balancing pathogen clearance, control of microbiota and host tissue damage, and that precise modulation of IL-10 functions in vivo could present therapeutic opportunities.

T helper 2 (T2) cells orchestrate type 2 immunity during protective antihelminth immunity and help restore tissue homoeostasis. Their misdirected activities against innocuous substances also underlie atopic diseases, such as asthma and allergy. Recent technological advances are uncovering novel insights into the molecular mechanisms governing T2 cell differentiation and function.

The rise in the prevalence of allergic diseases has become a global health burden. Allergic diseases are a group of immune-mediated disorders characterized by IgE-mediated conditions resulting from a type 2 helper T cell (Th2)-skewed immune response. This review aims to comprehensively summarize recent research on the roles of allergen immunotherapy (AIT) and biologics in allergic diseases. Specifically, we review the mechanisms of AIT and biologics in modulating innate and adaptive immunity involved in allergic disease pathogenesis, as well as their safety and efficacy in the treatment of allergic diseases. We also discuss current new AIT strategies such as recombinant allergen-based vaccines and allergen extract nanoencapsulation. Further research is needed to understand immune tolerance mechanisms beyond the Th2 pathway and to characterize immunological changes in responders and nonresponders to AIT or biologics. This additional research may uncover new targets for monitoring treatment responses and developing personalized treatment strategies for allergic diseases.

B cells experience extreme alterations in their metabolism throughout their life cycle, from naïve B cells, which have minimal activity, to germinal centre (GC) B cells, which proliferate at the fastest rate of all cells, to long-lived plasma cells with very high levels of protein production that can persist for decades. The underpinning of these transitions remains incompletely understood, and a key question is how utilisation of fuel source supports B cell metabolism. For example, GC B cells, unlike almost all rapidly proliferating cells, mainly use fatty acid oxidation rather than glycolysis. However, following differentiation to plasma cells, their metabolism switches towards a high rate of glucose consumption to aid antibody production. In this review, we discuss the key metabolic pathways in B cells, linking them to cellular signalling events and placing them in the context of disease and therapeutic potential.

Aging, metabolism, and immunity have long been considered distinct domains. Aging is primarily associated with the gradual decline of physiological functions, metabolism regulates energy production and maintains cellular processes, and the immune system manages innate and adaptive responses against pathogens and vaccines. However, recent studies have revealed that these three systems are intricately interconnected, collectively influencing an individual's response to stress and disease. This review explores the interplay between immunometabolism, T follicular helper cells, B cells, and aging, focusing on how these interactions impact immune function in the elderly.

Epithelial cells provide a first line of immune defense by maintaining barrier function, orchestrating mucociliary clearance, secreting antimicrobial molecules, and generating sentinel signals to both activate innate immune cells and shape adaptive immunity. Although epithelial alarmins play a particularly important role in the initiation of type 2 inflammation in response to allergens, the mechanisms by which epithelial cells sense the environment and regulate the generation and release of alarmins have been poorly understood. Recent studies have identified new sensors and signaling pathways used by barrier epithelial cells to elicit type 2 inflammation, including a novel pathway for the release of interleukin-33 from the nucleus that depends on apoptotic signaling. These recent findings have implications in the development of allergic diseases, from atopic eczema to food allergy, rhinitis, and asthma.

Inflammasomes are multiprotein signaling structures in the innate immune system that drive cell death and inflammatory responses. These protein complexes generally comprise an innate immune sensor, the adaptor protein ASC, and the inflammatory protease caspase-1. Inflammasomes are formed when a cytosolic sensor, also known as a pattern recognition receptor, senses its cognate ligand, which can include microbial components, endogenous damage/danger signals, or environmental stimuli. Inflammasome assembly leads to autoproteolytic cleavage and activation of caspase-1. This activation, in turn, induces proteolytic maturation and release of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the activation of the pore-forming molecule gasdermin D to induce cell death, known as pyroptosis. Recent studies have identified inflammasomes as integral components of larger cell death complexes, known as PANoptosomes. These PANoptosomes regulate PANoptosis, an innate immune cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting serine/threonine protein kinases. PANoptosome assembly and activation leads to cell lysis, inflammation, and the release of proinflammatory cytokines, damage-associated molecular patterns, and alarmins. In this review, we discuss the current understanding of different inflammasomes and their role in PANoptosomes.

Immunoglobulin E (IgE)-mediated allergic diseases are driven by high-affinity allergen-specific IgE antibodies. IgE antibodies bind to Fc epsilon receptors on mast cells, prompting their degranulation and initiating inflammatory reactions upon allergen crosslinking. While most IgE-producing plasma cells have short lifespans, and IgE memory B cells are exceedingly rare, studies have indicated that non-IgE-expressing type 2-polarized IgG memory B cells serve as a reservoir of IgE memory in allergies. This review explores the B cell populations underlying IgE-mediated allergies, including the cellular and molecular processes that drive IgE class switching from non-IgE memory B cells. It highlights emerging evidence from human studies identifying type 2 IgG memory B cells as the source of pathogenic IgE in allergic responses.

Emerging studies on the diet-immune axis have uncovered novel dietary immune regulators and identified crucial targets and pathways mediating the crosstalk between specific dietary components and diverse immune cell populations. Here, we discuss the recent discovery and mechanisms by which diet-derived components, such as vitamins, amino acids, fatty acids, and antioxidants, could impact immune cell metabolism, alter signaling pathways, and reprogram the overall cellular responses. We also note crucial considerations that need to be tackled to make these findings clinically relevant, acknowledging that our current understanding often relies on simplified models that may not adequately represent the intricate network of factors influencing the diet-immune axis at the whole organism level. Overall, our growing understanding of how diet shapes our defenses underscores the importance of lifestyle choices and illuminates the potential to fine-tune immune responses through targeted nutritional strategies, thereby fortifying the immune system and bolstering our defenses against diseases.

Five mammalian Toll-like receptors (TLR 3, 7, 8, 9, and 13) recognize nucleic acids (NA) and induce signals that control the function of multiple immune cell types and initiate both innate and adaptive immune responses. While these receptors enable recognition of diverse microbial threats, in some instances, they respond inappropriately to self-NA released from host cells and drive the development of autoimmune diseases. Specifically, activation of TLR7 and TLR8 by self-RNA and TLR9 by self-DNA has been linked to development of a collection of systemic autoimmune or autoinflammatory disorders, including systemic lupus erythematosus, systemic juvenile idiopathic arthritis, and macrophage activation syndrome. Here, we discuss recent progress in understanding how these receptors contribute to such diverse clinical phenotypes. We highlight how comparative studies between mice and humans have not only been beneficial in identifying key pathways relevant for disease but also reveal gaps in our understanding of disease mechanisms. We identify several challenges that we hope the field will tackle in the years ahead.