Trends Immunol
· 2026 May · PMID 42178195
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Substance use disorders are traditionally conceptualized as disorders of brain reward circuitry; however, accumulating evidence demonstrates that addictive substances exert profound and persistent effects on central and...Substance use disorders are traditionally conceptualized as disorders of brain reward circuitry; however, accumulating evidence demonstrates that addictive substances exert profound and persistent effects on central and peripheral immune and inflammatory systems. Opioids, psychostimulants, alcohol, nicotine, cannabinoids, and psychedelics modulate immune signaling across multiple organs, including the brain, gut, liver, lungs, skin, and systemic circulation. In parallel, drugs of abuse remodel neuroimmune communication both centrally and peripherally, altering interactions between neurons, glial cells, and immune populations. This review synthesizes clinical and preclinical evidence linking substance exposure to systemic inflammation, delineates shared cellular and molecular mechanisms across tissues, and highlights emerging paradigms of systemic neuroimmune crosstalk.
Grant writing is a career-defining skill that most researchers learn too late and without formal training. Here, we describe the integration of a structured, discipline-specific grant writing workshop into a postgraduate...Grant writing is a career-defining skill that most researchers learn too late and without formal training. Here, we describe the integration of a structured, discipline-specific grant writing workshop into a postgraduate immunotherapy course and show that it measurably improved student confidence, funding literacy, and practical readiness.
Upon leaving the protective microenvironment of the primary tumor, disseminating tumor cells (DTCs) must withstand immune surveillance on their own. Cassandras et al. recently demonstrated that activation of the glucocor...Upon leaving the protective microenvironment of the primary tumor, disseminating tumor cells (DTCs) must withstand immune surveillance on their own. Cassandras et al. recently demonstrated that activation of the glucocorticoid receptor pathway serves as a critical mechanism for immune evasion during metastatic outgrowth from DTCs.
The adaptive immune system (AIS) is traditionally viewed as a defensive vertebrate innovation forged by pathogen pressure. Yet many of its core features suggest it is a homeostatic, regulatory circuit, not simply a sophi...The adaptive immune system (AIS) is traditionally viewed as a defensive vertebrate innovation forged by pathogen pressure. Yet many of its core features suggest it is a homeostatic, regulatory circuit, not simply a sophisticated means of antimicrobial warfare. The horizontal transfer of mitochondria--endogenous endosymbiotic organelles-is a conserved mechanism for maintaining tissue homeostasis through metabolic rescue but can alter a cell's identity and provoke immune responses. We propose that escalating multicellular complexity accommodated mitochondrial mobility-and the inevitable intrinsic immunological danger it presents-through a complementary supervisory system with buffering (tolerance), contextualization (specificity), memory, and eliminatory capacities. This perspective reframes the AIS as a constitutive danger management network, integrating tissue homeostasis, metabolic surveillance, immune tolerance, and immunological defense.
Glycan-specific antibodies are classically associated with limited durability. In a recent Immunity article, Fryer et al. showed that repeated Streptococcus pyogenes exposure elicits glycan-specific germinal center respo...Glycan-specific antibodies are classically associated with limited durability. In a recent Immunity article, Fryer et al. showed that repeated Streptococcus pyogenes exposure elicits glycan-specific germinal center responses in tonsils despite reduced T cell help, revealing key limitations of anti-glycan immunity and opportunities to improve vaccine strategies against bacteria.
Itaconate is an immunomodulatory metabolite that links metabolism and inflammation. Li et al. uncover a mechanism by which itaconate and 4-octyl itaconate suppress cytokine signaling through the alkylation of tyrosine ki...Itaconate is an immunomodulatory metabolite that links metabolism and inflammation. Li et al. uncover a mechanism by which itaconate and 4-octyl itaconate suppress cytokine signaling through the alkylation of tyrosine kinase 2 and Janus kinase 1. This study reveals a direct metabolic control of inflammation and highlights its therapeutic potential in sepsis.
Sickness, or sickness behavior, is a state of altered physiology and behavior generated by the brain-immune axis during infection, which is generally assumed to contribute to host defense. Here, we examine this assumptio...Sickness, or sickness behavior, is a state of altered physiology and behavior generated by the brain-immune axis during infection, which is generally assumed to contribute to host defense. Here, we examine this assumption by framing sickness as organismal-scale immunity and explore predicted parallels with immunity at the cellular and tissue scales.
Placental biology is increasingly framed through a signaling paradigm in which maternal microbiome-derived mediators-rather than microbial colonization-affect the function of the interface. This review synthesizes eviden...Placental biology is increasingly framed through a signaling paradigm in which maternal microbiome-derived mediators-rather than microbial colonization-affect the function of the interface. This review synthesizes evidence that circulating microbial signals, including short-chain fatty acids, tryptophan-derived indoles, bile-acid-linked ligands, microbe-associated molecular patterns, and bacterial extracellular vesicles, are associated with placental vascular development, immune regulation, nutrient transport, and endocrine programs-processes central to pregnancy outcomes. We integrate mechanistic insights from gnotobiotic and supplementation models with limitations of human evidence and identify key translational gaps. The current evidence supports a model in which maternal microbial ecology shapes a network of circulating mediators that converge on interlinked placental pathways essential for placental function and fetal development.
It remains unclear how mitochondrial stress instructs the transcriptional programme of terminal T cell exhaustion. In a recent study, Xu et al. uncovered a proteasome-haem-BACH2 axis in which haem liberated from damaged...It remains unclear how mitochondrial stress instructs the transcriptional programme of terminal T cell exhaustion. In a recent study, Xu et al. uncovered a proteasome-haem-BACH2 axis in which haem liberated from damaged mitochondrial haemoproteins acts as a molecular messenger that couples mitochondrial injury to terminal T cell exhaustion.
Trends Immunol
· 2026 Apr · PMID 42025540
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Full text
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites. Recent studies have suggested numerous markers to define MAIT cells with distinct functional characteristics. This...Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites. Recent studies have suggested numerous markers to define MAIT cells with distinct functional characteristics. This review synthesizes available data to identify markers that distinguish type 1 and type 3 murine MAIT cells. Inflammation can alter the expression of these markers, reflecting the plasticity of MAIT cells, which is discussed further. Comparative analysis with human MAIT cells reveals that type 1 and type 3 subsets are not as apparent. Although these have been described as activation states, unique human MAIT cell subsets exist across various tissues. By establishing a consensus for how to categorize MAIT cells, this review facilitates future research on these important lymphocytes.
The macrophage disappearance reaction (MDR) was originally proposed to explain the loss of peritoneal macrophages in inflammation but has since been extended across tissues and diseases. MDR involves multiple processes,...The macrophage disappearance reaction (MDR) was originally proposed to explain the loss of peritoneal macrophages in inflammation but has since been extended across tissues and diseases. MDR involves multiple processes, including cell death, differentiation, loss of identity, and the formation of aggregates rendering the cells difficult to isolate. This spectrum of modalities, coupled with our increased understanding of how the microenvironment shapes macrophage identities, highlights the need to reassess MDR within the framework of modern macrophage biology. We postulate that rethinking MDR in the context of the tissue niche offers insights into macrophage dynamics and demonstrates that macrophage loss is not a passive outcome of inflammation but rather an active process shaping immune networks, tissue responses, and ultimately organ function.
Natural killer (NK) cells are part of the innate immune system and reside in multiple tissues. During steady-state conditions, they contribute to tissue homeostasis, while in disease settings, tissue-resident (tr) NK cel...Natural killer (NK) cells are part of the innate immune system and reside in multiple tissues. During steady-state conditions, they contribute to tissue homeostasis, while in disease settings, tissue-resident (tr) NK cells are positioned at the frontline of immune surveillance. Due to their exposure to local microenvironments, NK cells residing outside the bloodstream exhibit phenotypic, transcriptional, functional, and metabolic features that distinguish them from their circulating counterparts. In this review, we outline the defining characteristics of tr NK cells, discuss their recirculation potential, and summarize their functional and metabolic specialization across human tissues. Finally, using cancer as an example, we highlight how tr NK cells are altered in disease and how local tissue environments shape their functional states.
Immunogenic cell death (ICD) converts the death of a tumor cell into an event sensed by the immune system. Recent studies show that distinct ICD modalities, including immunogenic apoptosis, pyroptosis, necroptosis, and h...Immunogenic cell death (ICD) converts the death of a tumor cell into an event sensed by the immune system. Recent studies show that distinct ICD modalities, including immunogenic apoptosis, pyroptosis, necroptosis, and hybrid forms such as PANoptosis, release defined sets of danger signals and cytokines that reshape the immune composition of the tumor microenvironment. In this review, we examine how ICD activates antitumor immunity and which immune cell subsets drive these responses. We also discuss how the benefits of ICD rely on its acute and transient nature, whereas prolonged or chronic exposure to the same inflammatory cues can ultimately dampen immune activation and promote oncogenesis. Finally, we outline the role of ICD and its clinical relevance in combination with immunotherapies.
The central nervous system (CNS), once considered immune privileged, is, in fact, protected by a dynamic immune compartment located in the meninges. These immune cells are crucial for brain protection, controlling neuroi...The central nervous system (CNS), once considered immune privileged, is, in fact, protected by a dynamic immune compartment located in the meninges. These immune cells are crucial for brain protection, controlling neuroinflammation, and also supporting neural function. Recent studies show that meningeal immune cells, including myeloid and B cells, partly originate from the skull bone marrow, which communicates directly with the meninges via specialized skull channels identified in mice and humans. These channels allow immune cell trafficking and cerebrospinal fluid (CSF) exchange, positioning the skull marrow as a CSF-sensing niche. Therefore, understanding skull-meninges-brain interactions reveals a functional connection between the skull marrow and the CNS, offering new insights into neuroimmune regulation and potential therapeutic strategies in neuroinflammatory conditions.
Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has attracted considerable attention in tumor biology and cancer therapy. Beyond its intrinsic role in tumor suppression, ferroptos...Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has attracted considerable attention in tumor biology and cancer therapy. Beyond its intrinsic role in tumor suppression, ferroptosis greatly influences the tumor immune microenvironment. Ferroptotic tumor cells release damage-associated molecular patterns, oxidized lipid mediators, and nucleic acids, which can either activate or suppress antitumor immunity. Conversely, immune cells modulate tumor cell sensitivity to ferroptosis through the secretion of cytokines and metabolites. In this review, we summarize the current understanding of the interplay between ferroptosis and tumor immunity. Targeting ferroptosis may offer broad opportunities to enhance tumor immunotherapy.
Trained immunity (TRIM), a paradigm-shifting concept in immunology, refers to the long-term functional reprogramming of innate immune cells, enabling enhanced responsiveness to secondary challenges through metabolic and...Trained immunity (TRIM), a paradigm-shifting concept in immunology, refers to the long-term functional reprogramming of innate immune cells, enabling enhanced responsiveness to secondary challenges through metabolic and epigenetic remodeling. This phenomenon bridges the gap between innate and adaptive immunity, offering novel strategies for vaccine design that transcend traditional antigen-specific approaches. By exploiting the 'memorylike' properties of monocytes, macrophages, dendritic cells, neutrophils, and natural killer cells, next-generation vaccines aim to achieve broad-spectrum protection, prolonged durability, and heterologous immunity against pathogens and cancers. This review synthesizes recent advances in TRIM research in vaccines, focusing on its mechanisms, translational applications, and future directions in vaccinology.
Toll-like receptor-2 (TLR2) serves as an innate immune sensor that recognizes specific viral proteins, thereby initiating signaling pathways that can either enhance antiviral host defenses or induce pathological inflamma...Toll-like receptor-2 (TLR2) serves as an innate immune sensor that recognizes specific viral proteins, thereby initiating signaling pathways that can either enhance antiviral host defenses or induce pathological inflammatory responses. In this forum, we discuss the role of TLR2 and its agonists in enhancing antiviral and vaccine-induced immune responses.