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...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.
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 modul...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.
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 d...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.
Cassano A, Abbondanza D, Chong AS
… +1 more, Alegre ML
Trends Immunol
· 2025 Sep · PMID 40707326
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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...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.
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 ax...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.
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 b...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.
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 environmenta...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.
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 incr...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.
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 th...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.
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-...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.
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,...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. GZMKCD8 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 GZMKCD8 T cells, and discuss the potential of targeting their dysregulated activities to treat chronic inflammation and malignancies.
Trends Immunol
· 2025 Aug · PMID 40651882
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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 r...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.
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 alte...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.
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 rema...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.
Smith MH, Parker RR, Patrick KL
… +1 more, Courvan EMC
Trends Immunol
· 2025 Aug · PMID 40592687
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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 ti...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.
Trends Immunol
· 2025 Jul · PMID 40555565
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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 no...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.
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 c...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.
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 classificat...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.
Strine MS, Vahkal B, St Denis K
… +1 more, Konnikova L
Trends Immunol
· 2025 Jul · PMID 40518358
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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 e...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.
Trends Immunol
· 2025 Jul · PMID 40506286
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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...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.