De Leeuw et al. conducted human observational and murine studies to establish the combined role of parental aeroallergen sensitization and early-life respiratory syncytial virus infection in asthma development. The findi...De Leeuw et al. conducted human observational and murine studies to establish the combined role of parental aeroallergen sensitization and early-life respiratory syncytial virus infection in asthma development. The findings reveal synergistic effects driving immunological, pathological, and physiological changes resembling asthma, advancing the understanding of disease mechanisms and potential preventive targets.
Bile acids are cholesterol derivatives, generated by the coordinated intervention of human and bacterial genes, functioning as endogenous ligands for multiple transcription factors and receptors throughout the body. Whil...Bile acids are cholesterol derivatives, generated by the coordinated intervention of human and bacterial genes, functioning as endogenous ligands for multiple transcription factors and receptors throughout the body. While only two primary bile acids are generated by the human liver, the intestinal microbiota is the source of hundreds of secondary bile acids and microbially conjugated bile acids. Secondary bile acids regulate immune function throughout the body, promote the conversion of thyroid hormone, and regulate energy expenditure in muscle and adipose tissues, ultimately contributing to the beneficial effects of calorie restriction on human health and longevity. Here, we discuss recent advances in our understanding of secondary bile acids, the intestinal microbiota generating them, and their role in immune disorders.
Trends Immunol
· 2026 Mar · PMID 41771720
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During pregnancy, complex interactions of maternal immune cells and fetal extravillous trophoblasts (EVTs) orchestrate placentation, immune tolerance, and immune defense. This forum article highlights important discoveri...During pregnancy, complex interactions of maternal immune cells and fetal extravillous trophoblasts (EVTs) orchestrate placentation, immune tolerance, and immune defense. This forum article highlights important discoveries and outstanding questions on how the activation of decidual natural killer and T cells, through recognition of key EVT ligands, promotes placentation, tolerance, and immunity.
Macrophages are key in maintaining tissue homeostasis and controlling inflammation. To rapidly adapt their phenotype, they rely on JAK-STAT signaling pathways to convert extracellular cytokine cues into transcriptional r...Macrophages are key in maintaining tissue homeostasis and controlling inflammation. To rapidly adapt their phenotype, they rely on JAK-STAT signaling pathways to convert extracellular cytokine cues into transcriptional responses. Understanding how macrophages interpret disease-associated cytokine environments is therefore key for deciphering how inflammation is resolved or sustained.
Lactation is increasingly recognized as an immune-regulated process. Immune cells shape mammary gland development, coordinate tissue remodeling, and aid in milk production with lasting consequences for maternal health. H...Lactation is increasingly recognized as an immune-regulated process. Immune cells shape mammary gland development, coordinate tissue remodeling, and aid in milk production with lasting consequences for maternal health. Here, we summarize recent advances on the roles and dynamics of T cells in the mammary gland during lactation and beyond.
Dendritic cell (DC) maintenance and positioning are essential for their function in lymph nodes. Wu et al. identify gremlin1 (Grem1) fibroblastic reticular cells as critical source of niche-specific Fms-like tyrosine kin...Dendritic cell (DC) maintenance and positioning are essential for their function in lymph nodes. Wu et al. identify gremlin1 (Grem1) fibroblastic reticular cells as critical source of niche-specific Fms-like tyrosine kinase 3 ligand (Flt3L) for conventional DC maintenance in health and disease, highlighting stromal cells as key regulators of immunity.
The brain is no longer viewed as immunologically isolated but as an organ surrounded by dynamic border compartments that coordinate surveillance, drainage, and communication with the periphery. Key interfaces - including...The brain is no longer viewed as immunologically isolated but as an organ surrounded by dynamic border compartments that coordinate surveillance, drainage, and communication with the periphery. Key interfaces - including the meninges, blood-brain barrier, choroid plexus (ChP), and skull bone marrow - host specialized immune niches that regulate antigen sampling, leukocyte trafficking, and neuroimmune signaling. Recent advances in imaging and in single-cell and spatial profiling have revealed previously unrecognized cell types, migration routes, and barrier specializations that shape central nervous system (CNS) immunity in health and disease. Understanding how these border tissues sense, integrate, and modulate immune activity opens opportunities for therapeutically tuning neuroimmune responses at the brain's periphery while preserving parenchymal integrity.
Insights into T-cell biology in the central nervous system (CNS) have evolved from early neuroinflammatory models demonstrating the pathogenic potential of autoreactive T cells to recent human studies defining resident T...Insights into T-cell biology in the central nervous system (CNS) have evolved from early neuroinflammatory models demonstrating the pathogenic potential of autoreactive T cells to recent human studies defining resident T-cell populations in the healthy and diseased brain. We here discuss advances in postmortem brain tissue processing, flow cytometry, and transcriptional profiling revealing that human brain CD8 and CD4 T cells are tissue-resident memory T cells with distinct phenotypes shaped by CNS borders and parenchymal niches. These findings refine our understanding of CNS immune surveillance and provide a framework for dissecting T-cell contributions to multiple sclerosis.
Regulatory T cells (T) have gained renewed attention for their diverse roles beyond immune suppression. This review integrates recent discoveries on how tissue-resident T integrate immune, metabolic, and neural cues to m...Regulatory T cells (T) have gained renewed attention for their diverse roles beyond immune suppression. This review integrates recent discoveries on how tissue-resident T integrate immune, metabolic, and neural cues to maintain organ homeostasis and regeneration. Across adipose tissue, intestine, brain, and skin, T coordinate local networks that couple immune tolerance with metabolic balance and tissue repair. We further discuss therapeutic advances - including antigen-specific chimeric antigen receptor (CAR)/T cell receptor (TCR) T, interleukin 2 (IL-2) muteins, and metabolic modulation - that aim to harness T for treating autoimmunity and chronic inflammation. Together, these insights highlight T as central interpreters of tissue context and as promising targets for next-generation precision immunotherapy.
Di Pietro AA, Powley S, Perciballi E
… +3 more, Stewart M, Therrien M, Scott-Hewitt N
Trends Immunol
· 2026 Jun · PMID 41507006
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Bidirectional crosstalk between the immune and nervous systems, via 'neuroimmune circuits', regulates homeostatic and inflammatory responses essential for health. Microglia, long-lived brain macrophages, act as key hubs...Bidirectional crosstalk between the immune and nervous systems, via 'neuroimmune circuits', regulates homeostatic and inflammatory responses essential for health. Microglia, long-lived brain macrophages, act as key hubs integrating immune signals into coordinated brain responses by shifting into distinct functional states in response to local and systemic cues. In this review, we focus on how environmental signals shape these microglial states, how microglia influence other brain cells through both direct and indirect mechanisms, and emerging evidence of how microglia are impacted by, and respond to, peripheral changes. We highlight microglia as central players in systemic neuroimmune communication, influencing both brain and peripheral health, while outlining recent tools and key knowledge gaps to guide future research into mechanisms of neuroimmune circuit communication.
Interleukin-23 (IL-23) is a pleiotropic cytokine that maintains the delicate balance between tolerance to commensal microbiota and defense against pathogens at mucosal barriers. When dysregulated, IL-23 becomes a key dri...Interleukin-23 (IL-23) is a pleiotropic cytokine that maintains the delicate balance between tolerance to commensal microbiota and defense against pathogens at mucosal barriers. When dysregulated, IL-23 becomes a key driver of chronic inflammation, with therapeutics blocking this pathway being successfully harnessed in the clinic. In this review, we discuss recently uncovered biology of IL-23 in the context of mucosal immunity, which intimately links the role of this pathway to the pathophysiology of autoimmunity, chronic inflammation, and emerging functions in cancer. Through the lens of the cell types that respond to IL-23, the engaged effector programs, and the key functions in health and disease, we highlight recent advances and opportunities to better understand the dichotomous outcomes mediated by this cytokine.
Parity and lactation have long been recognised as protective factors in breast cancer, with notable risk reduction in triple negative breast cancer (TNBC). Recent work by Virassamy et al. suggests a tissue-specific, pers...Parity and lactation have long been recognised as protective factors in breast cancer, with notable risk reduction in triple negative breast cancer (TNBC). Recent work by Virassamy et al. suggests a tissue-specific, persistent immune surveillance underpins this effect, particularly in women who have also breastfed.
The advancement of immunotherapy faces significant challenges, including extending its benefits to a growing number of patients and enhancing its efficacy across different tumor types. In this context, γδ T cells emerge...The advancement of immunotherapy faces significant challenges, including extending its benefits to a growing number of patients and enhancing its efficacy across different tumor types. In this context, γδ T cells emerge as particularly promising candidates owing to their distinctive biological features such as MHC-independent activation, potent cytotoxicity, and capacity to bridge innate and adaptive immunity. Recently, advanced single-cell techniques have allowed detailed γδ T cell characterization in the tumor microenvironment (TME) and have emphasized their heterogeneity, mechanisms of activation, and response to immune checkpoint blockade (ICB). This review provides a comprehensive summary of recent advances in understanding γδ T cells in colorectal cancer (CRC), with a particular emphasis on their prognostic and therapeutic relevance in both primary tumors and metastatic disease.
Intestinal homeostasis is crucial for overall health, and its maintenance relies on a complex and delicate interplay between intestinal epithelial cells, the gut microbiota, and the immune system. Among immune components...Intestinal homeostasis is crucial for overall health, and its maintenance relies on a complex and delicate interplay between intestinal epithelial cells, the gut microbiota, and the immune system. Among immune components, group 3 innate lymphoid cells (ILC3s), which primarily reside in the intestinal microenvironment, play a crucial role in maintaining gut homeostasis. Through the expression of multiple effector molecules such as interleukin (IL)-22 and major histocompatibility complex class II (MHCII), ILC3s orchestrate intestinal epithelial responses and regulate innate and adaptive immunity, thereby collectively promoting a symbiotic host-microbiota relationship, supporting immune tolerance, and providing protection against pathogens. This review summarizes current understanding of ILC3 functions in gut homeostasis, highlights their interactions with the microbiota and other cell types, and outlines how aberrant ILC3 activity contributes to disease pathogenesis.
Estrogen receptor (ER) breast malignancies are poorly infiltrated by immune cells, hence exhibiting limited sensitivity to immune checkpoint inhibitors (ICIs). Recent data from Palomeque et al. demonstrate that ER signal...Estrogen receptor (ER) breast malignancies are poorly infiltrated by immune cells, hence exhibiting limited sensitivity to immune checkpoint inhibitors (ICIs). Recent data from Palomeque et al. demonstrate that ER signaling actively contributes to such an immunoevasive phenotype by preventing the nuclear factor LCOR from establishing an ICI-sensitive tumor microenvironment.
Trends Immunol
· 2026 Mar · PMID 41407649
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Pregnancy requires dynamic immune adaptations that balance tolerance, homeostasis, and defense at the maternal-fetal interface. Recent advances integrating findings from human placental samples with those from refined an...Pregnancy requires dynamic immune adaptations that balance tolerance, homeostasis, and defense at the maternal-fetal interface. Recent advances integrating findings from human placental samples with those from refined animal models now enable a detailed analysis of how cellular responses in mid and late gestation contribute to major obstetrical complications - with distinct clinical manifestations - such as preterm birth, fetal growth restriction, and pre-eclampsia. In this Opinion article we propose a unifying paradigm: the breakdown of maternal-fetal immune homeostasis. We highlight regulatory T cells and decidual macrophages as complementary regulators of antigen-specific tolerance and nonspecific homeostasis, whereas effector T cell infiltration in chronic placental inflammation and neutrophil-driven inflammation in acute chorioamnionitis exemplify pathological immune activation. Together, these examples illustrate how immune programs that sustain mid-to-late pregnancy, when dysregulated, drive pathology and open new therapeutic opportunities.
Trends Immunol
· 2026 May · PMID 41390307
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Recent discoveries reveal that inflammasome signaling in neurons extends beyond host defense to influence fundamental aspects of brain function, including synaptic plasticity, axon remodeling, and exosome-mediated interc...Recent discoveries reveal that inflammasome signaling in neurons extends beyond host defense to influence fundamental aspects of brain function, including synaptic plasticity, axon remodeling, and exosome-mediated intercellular communication. This review explores how basal neuronal inflammasome activity contributes to central nervous system (CNS) homeostasis and how heightened signaling in neurons drives neuroinflammatory and degenerative processes. Understanding these dual roles of neuronal inflammasomes provides new insights into neuroimmune crosstalk and identifies potential targets for modulating repair and inflammation in CNS injury and disease.
The developmental origins of health and diseases concept posits that early-life exposure to environmental adversities increases risks for diverse noncommunicable and infectious diseases. Among these adversities, maternal...The developmental origins of health and diseases concept posits that early-life exposure to environmental adversities increases risks for diverse noncommunicable and infectious diseases. Among these adversities, maternal malnutrition is a critical determinant of offspring health trajectories. Maternal malnutrition from preconception to lactation can durably alter cellular and tissue function in the offspring. We propose that tissue-resident macrophages (TRMs) act as central mediators of this developmental programming. Seeding tissues during embryogenesis, integrating metabolic and hormonal signals, and persisting throughout life, TRMs can encode maternal nutritional states into lasting tissue adaptations. We summarize how specific maternal diets program distinct TRM subsets and how programmed TRMs link maternal nutritional statuses to disease susceptibility. TRMs may offer early intervention targets to improve offspring health.
The intestinal epithelium functions as an immune-metabolic interface, integrating environmental signals to maintain systemic homeostasis. Intraepithelial lymphocytes (IELs), interspersed within the epithelial layer, form...The intestinal epithelium functions as an immune-metabolic interface, integrating environmental signals to maintain systemic homeostasis. Intraepithelial lymphocytes (IELs), interspersed within the epithelial layer, form a highly interactive network with intestinal epithelial cells (IECs) to coordinate barrier defense, immune tolerance, and metabolic regulation. IECs orchestrate IEL development, positioning, and functional programming. Reciprocally, IELs modulate epithelial physiology, nutrient uptake, and epithelial repair. Dysregulation of the IEL-IEC unit contributes to intestinal and extraintestinal pathologies. This review discusses current advances in IEL-IEC bidirectional communication, highlighting the influences of diet, microbial metabolites, and immune checkpoints on this interface. We propose a paradigm in which the IEL-IEC interplay functions as a key immunometabolic regulatory unit and represents a promising therapeutic target for systemic diseases.
The SARS-CoV-2 pandemic has drawn global attention to post-acute infection syndromes (PAIS), with millions affected by post-acute sequelae of COVID-19 (PASC, or Long COVID). While Long COVID is newly defined, PAIS have b...The SARS-CoV-2 pandemic has drawn global attention to post-acute infection syndromes (PAIS), with millions affected by post-acute sequelae of COVID-19 (PASC, or Long COVID). While Long COVID is newly defined, PAIS have been described for over a century following epidemic infections. Multiple pathogens - including influenza, Epstein-Barr virus, and Borrelia burgdorferi, among others - can precipitate persistent, poorly understood symptoms. Chronic illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have long been linked to infectious triggers. This recurring association highlights critical knowledge gaps and underscores the need for systematic investigation. Unlike prior pandemics, the current era offers advanced technologies and analytic tools to address these gaps. Defining the biology of Long COVID may yield broader insights into host-pathogen interactions and mechanisms of chronic illness.