Trends in Immunology

Tile reading "The Nobel Prize in Physiology or Medicine: Read our related articles" Cell Press braned with a NObel Prize medal diplayed on the right hand side.

Congratulations to the 2025 #NobelPrize in Physiology or Medicine winners Drs. Mary Brunkow, Fred Ramsdell, & Shimon Sakaguchi for their discoveries concerning peripheral immune tolerance.

View their related research published in #CellPress journals: spkl.io/63325AVK2R

The dichotomous role of IL-2: tolerance versus immunity Interleukin-2 (IL-2) is a well-known T-cell growth factor, which is traditionally implicated in the agonistic stimulation of immune responses. Recent work, however, has uncovered an unexpected functio...

🎉 Congratulations to #Nobel Prize awardees Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their groundbreaking discoveries about peripheral immune tolerance and #tregs
Trends in Immunology had the privilege of featuring their influential research over the years.👉 www.cell.com/trends/immun...

Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation It is controversial how cytotoxic T lymphocyte antigen (CTLA)-4, a co-inhibitory molecule, contributes to immunological tolerance and negative control of immune responses. Its role as an inducer of ce...

🎉 Congratulations to #Nobel Prize awardees Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their groundbreaking discoveries about peripheral immune tolerance and #tregs
Trends in Immunology had the privilege of featuring their influential research over the years.👉 www.cell.com/trends/immun...

Fas and FasL in the homeostatic regulation of immune responses Studies of the biological effects of Fas signaling, using transformed cell lines as targets, indicate that ligation of the Fas receptor induces an apoptotic death signal. Chronically activated normal ...

🎉 Congratulations to #Nobel Prize awardees Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their groundbreaking discoveries about peripheral immune tolerance and #tregs
Trends in Immunology had the privilege of featuring their influential research over the years.👉
www.cell.com/immunology/f...

A mother's touch: microbial guardians of early immune imprinting The evolution of the fetal immune system within the womb is a delicate balancing act: it is trained to not reject maternal antigens, while equipping itself with ‘learned’ immunity to survive and thrive in the outside world. In this opinion article, we propose that a deliberate maternal touch via immune and nutritional influences, orchestrated, in part, by microbiota-derived components, imprints the fetal immune system with the needed immune memory and epigenetic marks to navigate a far less nurturing outside world, including early microbial colonizers in the newborn’s intestine, pathogens and irritants, and allergens in food. We redefine the hygiene hypothesis to include prenatal maternal microbial exposures, priming fetal immune development for long-term fitness and reduced inflammatory/autoimmune disease risk.

A mother's touch: microbial guardians of early immune imprinting #immunology

Germinal centre B cell disruption by non-typhoidal Salmonella Salmonella enterica serovar Typhimurium (STm) represents a major global health burden. Strains endemic in sub-Saharan Africa cause life-threatening invasive non-typhoidal salmonellosis (iNTS) in vulnerable populations. Studies in the iNTS-like mouse model show that STm induces profound germinal centre (GC) disruption, impairing high-affinity, long-lived antibody and memory B cell formation – affecting nascent and pre-existing GC reactions. Lipopolysaccharide (LPS) and specific STm type 3 secretion effectors drive GC collapse, but the determining bacteria–host interactions are still unclear. Although STm induces an extrafollicular (EF) B cell response generating protective antibodies, their longevity remains unclear. With no licensed human vaccine for iNTS, we propose that vaccine strategies should consider ways to protect GC integrity and include GC parameters as endpoints in preclinical trials.

Germinal centre B cell disruption by non-typhoidal Salmonella #immunology

Potential impact of long-read sequencing on complement-mediated diseases The complement genes harbour genetic variants that affect numerous diseases; however, these genes are notoriously repeat-heavy, and these repeat regions are largely unexplored for disease-relevant genetic variation. Elucidating these ‘dark’ regions is now possible using long-read sequencing (LRS), enabling identification of novel disease-relevant genetic variants.

Potential impact of long-read sequencing on complement-mediated diseases #immunology

It was great working with you and the team. Good luck for your future endeavors!

Kupffer cells facilitate intrahepatic CD4 T cell help Intrahepatic immune responses are often insufficient to control hepatitis virus infections. A recent study by Venzin and colleagues demonstrates a detailed mechanism by which an intrahepatic tricellular network and the cytokine IL-27 can augment virus-specific immunity.

Kupffer cells facilitate intrahepatic CD4 T cell help #immunology

Balancing IL-17–mediated protection and IFN-γ–driven pathology at mucocutaneous barriers #immunology

Emerging insights into mosaic errors of immunity Mosaic errors of immunity (MEI) encompass a group of immune disorders caused by somatic or gonosomal gene variants affecting hematopoiesis and immune function. Although the causal role of mosaicism in monogenic immune disorders has been recognized for over two decades, our understanding of their pathogenesis, genotype–phenotype correlation and clonal evolution remains poor. In this review, we synthesize shared and distinct molecular determinants from the currently recognized MEI and provide a mechanistic framework for future research. Exploring the implications of mosaic genetic variation in patients with unexplained immune disorders could uncover novel, actionable genetic disorders. Moreover, the study of these rare ‘experiments of nature’ may shed light on cell-specific immune pathways, non-malignant clonal dynamics, and mosaic disorders more broadly.

Emerging insights into mosaic errors of immunity #immunology

Decoding immune aging at single-cell resolution Advances in single-cell sequencing have transformed our understanding of immune aging by enabling high-resolution dissection of age-associated changes in cellular composition and function. Recent years have seen a surge in studies leveraging single-cell multi-omics to chart immune trajectories across the human lifespan, uncovering previously unrecognized heterogeneity and functional shifts in peripheral immune cells. While these technologies offer unprecedented insights, they also pose significant technical and analytical challenges, including data integration across platforms and populations. In this review, we critically examine landmark studies, compare emerging immune aging clocks, and highlight opportunities for clinical translation. By decoding immune aging at single-cell resolution, we move closer to early detection of immunosenescence, personalized immunomodulation, and precision strategies to extend healthspan in aging populations.

Decoding immune aging at single-cell resolution #immunology

Nonclassical HLA and pseudogenes in maternal–fetal tolerance and cancer The immunological tolerance protecting the fetus from maternal rejection during pregnancy involves nonclassical human leukocyte antigen (HLA) class I molecules (HLA-G, HLA-E, HLA-F) interacting with maternal immune-inhibitory receptors. Cancers similarly exploit these molecules to evade immune detection and promote tumor progression. Pseudogenes within the major histocompatibility complex may modulate these pathways via noncoding RNA, gene conversion, or protein interactions, although their precise roles remain unclear. Furthermore, fetal–maternal microchimerism potentially reinforces maternal tolerance but could also influence susceptibility to autoimmune disorders or cancer. This review critically evaluates current experimental evidence, identifies knowledge gaps, and proposes therapeutic approaches targeting these pathways in oncology without compromising maternal–fetal tolerance.

Nonclassical HLA and pseudogenes in maternal–fetal tolerance and cancer #immunology

Keep your neutrophils close, but your mast cells closer Immune activity at the cerebrospinal fluid (CSF)–dura–brain interface regulates key functions of brain physiology. In two back-to-back papers, Mamuladze et al. and Kothari et al. show that dural mast cells (MCs) are strategically positioned to coordinate this regulation, controlling CSF flow dynamics and immune cell trafficking in allergy, meningitis, and stroke.

Keep your neutrophils close, but your mast cells closer #immunology

Transcriptional control of natural killer cell antitumor activity Natural killer (NK) cells protect from viral infection, cancer, and metastasis, and are emerging as valuable therapeutics for cancer treatment. NK-cell control of viral infection has been studied intensively, but less is known in the context of cancer. Multiple associative, preclinical, and early phase clinical studies have revealed the ability of NK-cell-based therapies to contribute to cancer control. Development of effective NK-cell therapeutics will be facilitated by a deeper understanding of the mechanisms controlling NK cell function across an array of cancer types and states. This review will focus on recent studies of the transcription factors that control NK cell function and their response to leukemia, solid tumors, and metastasis.

Transcriptional control of natural killer cell antitumor activity #immunology

It was nice working with you, Martina!

Mitochondrial lipid metabolism in tumor immunosurveillance and evasion Mitochondrial lipid metabolism plays a pivotal role in tumor immunosurveillance and immune evasion. This review explores how mitochondrial regulation shapes immune cell metabolism within the tumor microenvironment (TME), focusing on the antitumor effects of the mitochondrial-fueled immune response and the detrimental impact of impaired mitochondrial function on immune cell cytotoxicity. Although current studies support this dual role, critical gaps remain, including how immune cells adapt differently to the lipid-rich TME, and how therapies can target lipid metabolism without harming immune memory. By synthesizing current findings and highlighting these uncertainties, this review highlights mitochondrial lipid metabolism as a promising therapeutic axis in cancer immunotherapy.

Mitochondrial lipid metabolism in tumor immunosurveillance and evasion #immunology

‘Smelling’ lipid cues: chemosensory receptors tune tumor-associated macrophage behavior Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment (TME), but their heterogeneity, driven by tumor-derived cues, poses challenges for therapeutic targeting and underscores the need for precise macrophage reprogramming strategies. Through a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen, Marelli et al. identified chemosensors as lipid-sensing regulators of macrophage activity, revealing new therapeutic avenues.

‘Smelling’ lipid cues: chemosensory receptors tune tumor-associated macrophage behavior #immunology

🚀 The September issue of Trends in Immunology is out! The cover features an Opinion article on early life circadian rhythms shaping immunity 🍼⏰. Plus, expert reviews on T cell tolerance, mitochondria in immunity, and more. Dive into the latest insights! 🔗 www.cell.com/trends/immun...
#Immunology

Uncovering the evolving arms race between host immunity and HIV-1 Despite an effective combination of antiretroviral therapy, HIV persists as a lifelong infection and global health threat. The human host equips restriction factors and interferon (IFN)-stimulated genes that target every step of the viral life cycle. However, HIV-1 has evolved a coordinated immune evasion strategy using a limited set of accessory proteins with distinct antagonistic functions. This functional division of labor allows HIV-1 to disable key immune pathways and ensure persistence. Here, we explore the molecular interplay between host defenses and HIV-1, organizing antiviral factors by viral life cycle stage. We further reframe viral immune evasion as a strategic division of labor among accessory proteins each adapted to target specific host defenses, offering insights for next-generation therapies.

Uncovering the evolving arms race between host immunity and HIV-1 #immunology

Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases Autoimmune diseases arise from genetic and environmental factors that disrupt immune tolerance. Recent studies highlight the role of myeloid cell immunometabolism, particularly mitochondrial dysfunction, in driving autoimmunity. Mitochondria regulate energy homeostasis and cell fate; their impairment leads to defective immune cell differentiation, abnormal effector activity, and chronic inflammation. We propose that chronic metabolic stress reprograms myeloid cells, fueling a vicious cycle of cell death and immune activation. Over time, this may induce several states of maladaptation in myeloid cells. Viewing autoimmune disease through a metabolic lens offers new insight into disease mechanisms and highlights potential therapeutic opportunities targeting mitochondrial function to restore immune balance.

Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases #immunology

Biomechanic regulation of neutrophil extracellular traps in the cardiovascular system Neutrophil extracellular trap (NET) formation, or NETosis, is a key innate immune response that contributes to cardiovascular diseases, including vascular inflammation, atherosclerosis, and thrombosis. In the cardiovascular system, neutrophils encounter mechanical cues such as shear stress, matrix stiffness, and cyclic stretch that influence their activation and NET release. This review examines emerging evidence linking altered mechanotransduction to dysregulated NETosis in vascular aging and cardiovascular pathology. We also highlight intracellular signalling pathways by which neutrophils sense and respond to mechanical stress. Understanding how biomechanical cues regulate NETosis may uncover novel therapeutic opportunities to control inflammation in cardiovascular disease without compromising host defence.

Biomechanic regulation of neutrophil extracellular traps in the cardiovascular system #immunology

Gut microbiota-specific T cell subset drives CNS inflammation Gut dysbiosis and intestinal inflammation may contribute to neurological disorders through the gut–brain axis. A recent report by White et al. uncovered that intestinal inflammation triggers the migration of microbiota-specific CD4+ T cells to the brain, where they drive neuroinflammatory responses via IL-23R/GM-CSF.

Gut microbiota-specific T cell subset drives CNS inflammation #immunology

Mitochondria and lysosomes in T cell immunometabolism Metabolic reprogramming and signaling are key orchestrators of T cell immunity. Recent studies have illustrated important roles for intracellular organelles, especially mitochondria and lysosomes, in enforcing T cell metabolism and signaling in response to various extracellular cues. As such, mitochondrial and lysosomal function contributes to adaptive immunity by regulating T cell activation, differentiation, and functional adaptation. In this Review, we discuss how the interplay between organelle biology and metabolism instructs T cell-mediated immunity, with a particular focus on mitochondria and lysosomes. We also summarize how mitochondria and lysosomes, or their crosstalk with other organelles, orchestrate downstream signaling processes and functional reprogramming of T cells. We conclude with a discussion of the pathophysiological outcomes associated with dysregulation of these organelles.

Mitochondria and lysosomes in T cell immunometabolism #immunology

Molecular mimicry as a driver of T cell-mediated tumour immunity Recently, a large pool of antigens derived from viral and bacterial microorganisms showing molecular mimicry with tumour-cell-expressed antigens was identified. These antigens can be presented by MHC molecules and elicit T cells that are crossreactive with microbial antigens and tumour-cell-associated antigens. In the setting of metastatic melanoma, such T cells can contribute to the response induced by immune checkpoint blockade therapy. Here, the current understanding of molecular mimicry in T cell-mediated tumour immunity and how this might be exploited for developing new preventive and therapeutic approaches for cancer is described. In particular, the literature on the concept and evidence of molecular mimicry in cancer is reviewed, covering the whole translational spectrum, from the antigen discovery strategy to the clinical evaluation.

Molecular mimicry as a driver of T cell-mediated tumour immunity #immunology

Common origins of autoimmune diseases and lymphoid malignancies Interactions between autoimmune disorders and lymphoid malignancies have long been recognized; for instance, with prominent autoimmune manifestations in B- and T-cell lymphomas and an increased risk of lymphoma development in individuals with autoimmune diseases. More recently, several lines of evidence have shown that these two disease types have shared origins, defined by common genetic lesions and pathogenic cell states. Recent work suggests that the safeguards that protect normal lymphocyte development and adaptive immunity against the development of autoimmune diseases and lymphoid malignancies are based on similar sensing mechanisms of pathological lymphocytes. Here, we propose that mechanisms of negative selection that are designed to eliminate autoreactive lymphocytes also operate in suppressing the development of lymphoid malignancies.

Common origins of autoimmune diseases and lymphoid malignancies #immunology

News from the T cell trogocytosis front T cells can exchange parts of their plasma membrane along with membrane-associated proteins through trogocytosis. During trogocytosis only certain subsets of membrane-associated proteins seem to be exchanged suggesting a fine-tuned mechanism regulating the selection of what can be transferred. In this review, we describe potential models of trogocytosis and discuss mechanisms that could regulate this process in T cells. Additionally, we delve into how exchanged proteins polarize on the surface of recipient cells, discuss how trogocytosis allows T cells to acquire new functions, and summarize ways to modulate this process in T cells. Understanding trogocytosis can help us better understand the immune response and develop more effective immunotherapies.

News from the T cell trogocytosis front #immunology

Balancing immunity: disease risk mutation can be beneficial An allelic variant of the autophagy gene ATG16L1 (T300A) is a genetic risk factor for Crohn’s disease. However, over 50% of the global population carries at least one copy. Yao et al. have demonstrated a heterozygote advantage, where the pathogen-protective effect of one allele may outweigh the disease risk in homozygotes.

Balancing immunity: disease risk mutation can be beneficial #immunology

Inosine boosts infant antiviral immunity Early antibiotic exposure disrupts the gut microbiota, impairing newborn antiviral immunity. Stevens et al. uncover that inosine, a metabolite produced by gut bacteria, restores the function of antiviral T cells by modulating gene regulation, boosting lung immune defenses against respiratory viruses.

Inosine boosts infant antiviral immunity #immunology

Advances in human myeloid-engrafting NSG-SGM3 and MISTRG mice Humanized mouse models with transgenic expression of human myelopoiesis-supporting growth factors have enhanced human myeloid cell engraftment and improved the study of human innate immune responses. Here, we discuss the remaining challenges associated with studying innate immunity in humanized NSG-SGM3 and MISTRG mice, as well as potential advances to overcome them.

Advances in human myeloid-engrafting NSG-SGM3 and MISTRG mice #immunology