Trends in Immunology

Targeting WSTF degradation to resolve chronic inflammation Chronic inflammation drives diseases like osteoarthritis and MASH, yet its molecular distinction from acute inflammation remains unclear. In a recent Nature study, Wang et al. revealed that chronic stress triggers WSTF degradation via nuclear autophagy, amplifying NF-κB responses. Blocking this pathway attenuates chronic inflammation while sparing acute immunity.

Targeting WSTF degradation to resolve chronic inflammation #immunology

Cell-intrinsic CD4 T cell tolerance: a new frontier in therapy? CD4 T cell tolerance is essential for immune homeostasis but its mechanisms remain unclear. Although regulatory T cells (Tregs) mediate T cell-extrinsic tolerance, this review emphasizes the CD4 T cell-intrinsic pathways – anergy and exhaustion – that are triggered by suboptimal or persistent antigen stimulation. These states share transcriptional and epigenomic features across contexts such as cancer, pregnancy, and transplantation. Instead of being distinct, they form a spectrum of tolerance with potential for therapeutic targeting. CD154 has re-emerged as a promising target, although memory T cell tolerization remains challenging. A deeper understanding of what sustains or reverses CD4 T cell tolerance is key to designing treatments that induce/maintain tolerance in autoimmunity and transplantation, or restore functionality in cancer and chronic infection.

Cell-intrinsic CD4 T cell tolerance: a new frontier in therapy? #immunology

Gut microbiota–host post-translational modification axis in immunometabolic diseases Communication between the gut microbiota and host post-translational modifications (PTMs) has been extensively characterized, and recent evidence delineates a functionally integrated gut microbiota–host PTM axis. This axis is not only essential for maintaining metabolism homeostasis but also plays diverse roles in regulating disease pathogenesis. In this review we discuss the emerging effects of microbial modulation of host PTMs by regulating substrate provisioning and enzyme activity. We also highlight the latest understanding of diverse microbiota-regulated PTMs in immune cell fate decision. Finally, we summarize the current understanding of how dysbiosis-induced PTM dysregulation drives pathologies in inflammatory bowel disease (IBD), obesity-related diseases, rheumatoid arthritis (RA), chronic kidney disease (CKD), and colorectal cancer (CRC). We also propose targeted strategies to restore homeostasis through the microbiota–PTM axis.

Gut microbiota–host post-translational modification axis in immunometabolic diseases #immunology

Primed to be primed: a new, second phase CD8 T cell activation and acquisition of cytolytic activity, which is essential for adaptive immunity, begins with priming in the lymph node (LN). Jobin et al. recently identified a second, delayed priming phase driven by competition with regulatory T cells for IL-2, revealing a rate-limiting step with significant clinical implications.

Primed to be primed: a new, second phase #immunology

Breaking tolerance: an update of Treg dysfunction in autoimmunity FOXP3+ regulatory T cells (Tregs) are essential for maintaining immune tolerance, and their dysfunction is a hallmark of autoimmune diseases. Recent studies have identified key transcriptional, metabolic, and environmental drivers of Treg instability and loss of function. Understanding these mechanisms opens new avenues for therapeutic interventions aimed at restoring immune homeostasis in autoimmunity.

Breaking tolerance: an update of Treg dysfunction in autoimmunity #immunology

Enlightening Per2-suasive role of neutrophils in antibacterial immunity Neutrophil numbers fluctuate over time, peaking during active phases to enhance immunity. The molecular link between circadian signals and cellular clocks remains unclear. Yi Du et al. show that light-regulated Per2 increases reactive oxygen species (ROS) production and bacterial killing in zebrafish neutrophils by controlling Hmgb1 expression, highlighting the impact of light on immune function.

Enlightening Per2-suasive role of neutrophils in antibacterial immunity #immunology

Low-dose IL-2 reinvigorates the immunoguardians of neurodegenerative diseases Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease caused by motor neuron loss. In a recent Phase 2b trial, Bensimon and colleagues report that the addition of low-dose interleukin 2 (LD-IL-2) immunotherapy to standard of care (SOC) shows promise in enhancing immune tolerance and improving survival in individuals with slower disease progression.

Low-dose IL-2 reinvigorates the immunoguardians of neurodegenerative diseases #immunology

Development of a circadian immune system Circadian rhythms are key regulators of immune functions. These endogenous oscillations help to maintain immune homeostasis, regulate responses to pathogens, and shape vaccine efficacy. Recent studies further indicate that they are of clinical relevance for cancer immunotherapies. While circadian immune rhythms are thus recognized to be important in adults, it is unknown at what developmental stage these rhythms begin to manifest. In this opinion article we review the development of circadian rhythms in the immune system in both rodents and humans, with a focus on their interactions during the perinatal period. Understanding their emergence in early life may help guide time-based clinical interventions for infants.

Development of a circadian immune system #immunology

Repurposing of old drugs for unleashing innate immunity Pharmacological activation of the stimulator of interferon genes (STING) pathway triggers inflammatory innate immune responses to potentially reinvigorate tumor immunogenicity. Recent work by Dang et al. revealed an alternative paradigm: a clinically approved old drug was repurposed to boost STING signaling and immune activation via a mode of action distinct from that of conventional STING agonists.

Repurposing of old drugs for unleashing innate immunity #immunology

Neuro–immune crosstalk: focus on innate lymphoid cells Neuro–immune crosstalk regulates inflammation and host metabolism via neural modulation of innate lymphoid cells (ILCs). Significant knowledge gaps remain regarding the signaling pathways, regulators, and physiological relevance of these interactions in human health and disease. Future studies leveraging innovative tools promise new insights and therapies for inflammatory and metabolic diseases.

Neuro–immune crosstalk: focus on innate lymphoid cells #immunology

GZMK+CD8+ T cells: multifaceted roles beyond cytotoxicity CD8+ T cells, traditionally recognized for their cytotoxic role in eliminating infections and malignancies, are now known to exhibit significant functional heterogeneity, as revealed by single-cell genomics. Among these, granzyme-K-expressing (GZMK+) CD8+ T cells represent a distinct subset characterized by low cytotoxicity but heightened proinflammatory activity, by contrast with their granzyme-B-expressing (GZMB+) counterparts with high cytotoxicity. GZMK+CD8+ T cells are often more abundant in inflammatory diseases, cancer, and age-related inflammation (inflammaging). These cells interact with stromal cells, activate the complement cascade, and perpetuate inflammation, highlighting their emerging therapeutic significance. We review the latest advances in the biology and pathological roles of GZMK+CD8+ T cells, and discuss the potential of targeting their dysregulated activities to treat chronic inflammation and malignancies.

GZMK+CD8+ T cells: multifaceted roles beyond cytotoxicity #immunology

Border-associated macrophages: guardians of vascular homeostasis The border tissues of the brain harbor specialized immune cells known as border-associated macrophages (BAMs), which have vital roles at these interfaces. However, factors governing their development and maintenance remain elusive. In a recent study, Van Hove et al. elegantly demonstrated that interleukin (IL)-34 is critical for sustaining BAMs and enabling their regulation of vascular function.

Border-associated macrophages: guardians of vascular homeostasis #immunology

Plans within plans: post-transcriptional regulation governs macrophage responses Macrophages are sentinels and first responders of the innate immune system. By sensing danger signals, they initiate and amplify inflammatory and regenerative cascades to control appropriate responses to pathogens and tissue damage. Transcriptional activation of macrophage gene expression has been studied extensively, but macrophage responses also rely on regulation of mRNAs following transcription. In this review we discuss mechanisms of post-transcriptional regulation that alter macrophage gene expression programs in profound and sometimes surprising ways. We explore how these control nodes are layered to form complex and dynamic circuits, discuss their role in disease, and conclude by outlining opportunities for future study of post-transcriptional regulation in macrophages.

Plans within plans: post-transcriptional regulation governs macrophage responses #immunology

Infusion of neutralization into Lassa vaccine design Lassa virus (LASV), which causes deadly Lassa fever (endemic in Western Africa), is a priority pathogen and a global health threat. Current vaccine candidates protect LASV-challenged animals through T cell immunity or non-neutralizing IgG/Fc receptor-mediated functions in the absence of potent neutralization. Neutralizing antibodies (nAbs), applied through passive immunization, also provide broad and complete protection against LASV. Rational design of LASV glycoprotein complex (GPC), the primary target for adaptive immunity, overcomes prior challenges to elicitation of nAbs caused by the dense glycan shield, metastability, and heterogeneity of GPC. Well-engineered GPC immunogens, in combination with advanced immunization methods and existing clinical trial phase vaccine candidates, provide a possibility to infuse neutralizing activity into complementary mechanisms of immune protection delivered by LASV vaccination.

Infusion of neutralization into Lassa vaccine design #immunology

Cryptic but critical: non-canonical antigens in cancer immunotherapy Two recent studies, by Ely et al. and Apavaloaei et al., revealed that non-canonical antigens derived from unmutated, noncoding regions dominate the immunopeptidome of many cancers. Here, we discuss how this challenges conventional mutation-centric immunotherapies and highlight emerging strategies, including cryptic antigen- and TCR-targeted vaccines, as promising new clinically relevant paths in personalised and off-the-shelf cancer immunotherapy.

Cryptic but critical: non-canonical antigens in cancer immunotherapy #immunology

The T cell subsetting challenge Exploiting specific T cell subset properties bears potential for T cell therapies but is complicated by inconsistencies in T cell subset definitions and markers. Here, we discuss causes for the definition and classification complexities to provide a handle for how to navigate the T cell subset jungle.

The T cell subsetting challenge #immunology

Exploring mucosal immune development and function in utero Multiomics advances have led to breakthroughs in understanding human early life immunity. Adaptive memory immune cells have been detected in fetal tissue extremely early in gestation, where they may respond to maternal exposures. These promising findings lay the groundwork for future research on the lifelong impact of early immune development.

Exploring mucosal immune development and function in utero #immunology

A physiological perspective on neuroimmune tissue innervation Organisms must adapt to unpredictable environmental perturbations. We propose that the immune system, which can be redistributed across tissues (‘immune innervation’), cooperates with the nervous system to form a larger integrative network that can maximize the number of adaptive physiologic states to a given perturbation.

A physiological perspective on neuroimmune tissue innervation #immunology

Restraining the killers: regulation of T cell quiescence #immunology

Lactate trains immunity Understanding the mechanisms implicated in the establishment of trained immunity could aid the design of novel therapeutic approaches. By studying Bacille Calmette-Guerin (BCG) vaccination in a human cohort, Ziogas and colleagues demonstrate the role of lactate generation and its use for histone lactylation as a key mechanism for establishing innate immune memory.

Lactate trains immunity #immunology

Microglia replacement: from monocytic origin to therapy Microglia replacement is reshaping neurodegenerative disease therapy, yet its key prerequisites remain unclear. In the current issue of Immunity, Aisenberg et al. and Bastos et al. reveal how developmental origin influences monocyte engraftment into the brain, and demonstrate the therapeutic potential of monocyte-based interventions in a monogenic neurological disease.

Microglia replacement: from monocytic origin to therapy #immunology

YTHDF2: a key RNA reader and antitumor target N6-methyladenosine (m6A) is a key mRNA modification influencing mRNA stability and translation. YTHDF2, a major m6A ‘reader’, was initially recognized for promoting mRNA decay but is now also known to enhance translation by binding to methylated mRNAs. YTHDF2 maintains the function of immune suppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), while also supporting cytotoxic immune cells, including natural killer (NK) and CD8+ T cells. Additionally, YTHDF2 acts as a tumor-intrinsic regulator orchestrating tumor immune evasion. Its multifaceted roles in tumor immunity make YTHDF2 a promising yet challenging therapeutic target. This review explores the complex roles and mechanisms of YTHDF2 in cancers, immune regulation, and tumor immune evasion and highlights emerging therapeutic strategies that target YTHDF2.

YTHDF2: a key RNA reader and antitumor target #immunology

Evolutionarily ancient functions of enzymatic TIR proteins in innate immunity Proteins with a Toll/interleukin-1 receptor/resistance (TIR) domain are among the most ancient immune regulators and include well-known pattern recognition receptors (PRRs). A specialized subset of TIR domain proteins are enzymes that predominantly use nicotinamide adenine dinucleotide (NAD+) to generate second messenger metabolites. These enzymatic TIR proteins have essential roles in bacteria, plant, and animal immunity. The mechanism of activation of these TIR proteins, conserved across Kingdoms, involves oligomerization into higher-ordered structures, which activates their intrinsic enzymatic activity. Here, we review the functions of enzymatic TIR proteins in innate immunity in bacteria, plants, and animals. This work offers insights into the evolutionary origins of immunity itself and defines fundamental principles of immune surveillance across the Tree of Life.

Evolutionarily ancient functions of enzymatic TIR proteins in innate immunity #immunology

Causes and consequences of T cell DNA damage Although DNA damage is a common cellular event, T cells experience significant genotoxic stresses because of rapid antigen-stimulated expansion and their presence in various nonlymphoid microenvironments. In addition to the well-established link between genomic instability and malignancy, recent genomic studies have uncovered a substantial mutational burden in nonmalignant T cells in both normal aging and disease contexts. Furthermore, genomic damage in T cells is accelerated in autoimmune diseases and in older individuals because of both intrinsic and extrinsic factors. This review highlights the different genotoxic stressors affecting T cells and the detrimental effects of persistent DNA damage and identifies the most critical knowledge gaps.

Causes and consequences of T cell DNA damage #immunology

Lung tumor immunity: redirecting macrophages through infection-induced inflammation Macrophages play a central role in maintaining tissue homeostasis and in surveillance against pathogens and disease. In the lung, they can adopt either proinflammatory or anti-inflammatory states depending on the nature of the stimulus. As the predominant immune cells in both the lung tumor microenvironment and in sites of lung infection, the functional plasticity of macrophages makes them key players in determining disease outcome. Accurately defining their inflammatory profiles offers an opportunity to reprogram infection-associated macrophages towards enhanced tumor-killing phenotypes. This review explores how acute inflammation can drive macrophage-mediated antitumor immunity and highlights key molecules and signaling pathways that may be leveraged to therapeutically modulate macrophage function.

Lung tumor immunity: redirecting macrophages through infection-induced inflammation #immunology

Using TCR-CAR dual signaling for precise cancer targeting Recently, Kondo et al. engineered the coexpression of a T cell receptor (TCR) and a chimeric antigen receptor (CAR) and developed an antagonism-enforced braking system where TCR signals both enhance and inhibit CAR activation. This work may enable rational design of CAR-T agents that limit toxicity to healthy tissue.

Using TCR-CAR dual signaling for precise cancer targeting #immunology

The microglial lineage: present and beyond Emerging studies demonstrate the presence of cells with microglial features in peripheral tissues. Here, we propose using the term ‘microglial lineage’ to categorize both these cells and classical microglia. Microglial lineage cells are resident immune cells with a microglial molecular phenotype and ontogeny that exhibit diverse tissue distribution and functions.

The microglial lineage: present and beyond #immunology

Poxvirus structural biology for application to vaccine design The upsurge of mpox (formerly known as monkeypox) in Africa and its global spread highlight the need for improved vaccines. The development of new recombinant vaccines, including mRNA and protein nanoparticles, depends on understanding the biology of poxviruses and selecting the most protective immunogens. Animal studies demonstrate that vaccines need to target the antigens of both infectious forms – the mature virion and the enveloped virion – which display surface proteins responsible for cell entry and cell-to-cell spread, respectively. Although some of these proteins have been shown to induce protective antibodies, others including most of those that are essential for membrane fusion remain to be tested. We review the structures of orthopoxvirus surface proteins as a guide to the selection of optimal antigens for recombinant vaccines.

Poxvirus structural biology for application to vaccine design #immunology

mRNA vaccines: miRNA-based controlled biodistribution and directed adjuvantation The development of ionizable mRNA-lipid nanoparticle (mRNA-LNP) nucleic acid carriers facilitated the clinical translation of the Coronavirus 2019 (COVID-19) mRNA vaccines BNT162b2 and mRNA-1273. Here, we discuss insights into rational improvements to mRNA vaccines, focusing on LNP modifications for mRNA-LNP biodistribution control, miRNA-based biodistribution control of encoded transcripts, and precision adjuvantation strategies.

mRNA vaccines: miRNA-based controlled biodistribution and directed adjuvantation #immunology

Inflammasomopathies: mechanisms and disease signatures Inflammasomes form in response to infection, cellular stress, or damage. Gain-of-function (GOF) mutations in inflammasome receptors have been identified as the underlying cause of severe inflammatory diseases, termed 'inflammasomopathies'. Recently, molecular interrogation of these diseases revealed several distinctions at the level of the tissue affected, the inflammatory mediators that drive disease progression, and the contribution of programmed cell death. In this review we discuss key emerging differences across inflammasomopathies and the distinct inflammatory patterns seen in patients. We discuss how programmed cell death influences the progression of inflammasomopathies and the role of plasma membrane rupture. Understanding the molecular disease signatures across inflammasomopathies provides crucial insights into identifying and treating the underlying disease and opens new avenues for therapeutic interventions.

Inflammasomopathies: mechanisms and disease signatures #immunology