Mayassi and colleagues utilized spatial transcriptomics to create a comprehensive blueprint of the mouse gut, exploring its adaptability and resilience under perturbed conditions. Their work highlights the adaptive capab...Mayassi and colleagues utilized spatial transcriptomics to create a comprehensive blueprint of the mouse gut, exploring its adaptability and resilience under perturbed conditions. Their work highlights the adaptive capabilities of the murine gut's regionalized structure, providing insights into how it functions in a coordinated manner and how it responds to external challenges.
Chronic inflammatory diseases show significant heterogeneity in their phenotypes, with diverse immune cells and mediators interacting in response to various stimuli. This review proposes the concept of the 'inflammazone'...Chronic inflammatory diseases show significant heterogeneity in their phenotypes, with diverse immune cells and mediators interacting in response to various stimuli. This review proposes the concept of the 'inflammazone' framework - which maps the distribution of immune components driving disease pathogenesis - using sarcoidosis and psoriasis as examples. Sarcoidosis features granulomatous inflammation with macrophages and CD4 T cells, which can spread to lymph nodes and other organs. Psoriasis, affecting primarily the skin, involves Th1, Th17, and Th22 pathways with CD8 T cells and dendritic cells. Human sarcoidosis exhibits geographic and racial variability, while psoriasis shows varying morphologies and disease courses. Sarcoidosis has more extensive distal immune signaling, whereas psoriasis remains more localized. Understanding the inflammazone is crucial for advancing personalized treatments for inflammatory diseases.
Trends Immunol
· 2025 Feb · PMID 39875238
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Lim and colleagues demonstrate that synNotch transcriptional circuits engineered into T cells can be used to precisely control location-specific expression of payloads responding to antigen triggers, thus locally inhibit...Lim and colleagues demonstrate that synNotch transcriptional circuits engineered into T cells can be used to precisely control location-specific expression of payloads responding to antigen triggers, thus locally inhibiting unwanted immunity or neuroinflammation. With no off-tumor toxicity or systemic immunosuppression upon elimination of mouse brain tumors, this approach can achieve better efficacy than anticipated.
Trends Immunol
· 2025 Feb · PMID 39855990
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Ovarian cancer (OC) is the most lethal gynecologic malignancy, characterized by multiple histological subtypes, each with distinct pathological and clinical features. Current treatment approaches include cytotoxic chemot...Ovarian cancer (OC) is the most lethal gynecologic malignancy, characterized by multiple histological subtypes, each with distinct pathological and clinical features. Current treatment approaches include cytotoxic chemotherapies, poly(ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, hormonal therapy, immunotherapy, and antibody-drug conjugates (ADCs). In this review we discuss immune evasion mechanisms in OC and the role of genetics, the tumor microenvironment, and tumor heterogeneity in influencing these processes. We also discuss the use of immunotherapies for OC treatment, either alone or in combination with other anticancer agents, with a focus on their clinical outcomes. Finally, we highlight emerging immunotherapies that have either succeeded or are on the verge of significantly impacting cancer treatment, and we discuss their potential utility in the effective treatment of OC.
Trends Immunol
· 2025 Feb · PMID 39843310
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Conventional dendritic cells (cDCs) are sentinels of the mammalian immune system that sense a wide range of danger and homeostatic signals to induce appropriately targeted T cell immune responses. Traditionally classifie...Conventional dendritic cells (cDCs) are sentinels of the mammalian immune system that sense a wide range of danger and homeostatic signals to induce appropriately targeted T cell immune responses. Traditionally classified into two main subsets, cDC1 and cDC2, recent research shows that cDC2s exhibit significant heterogeneity and can be further subdivided. Studies in mice and humans show that, beyond their ontogeny, cDC2s acquire dynamic and tissue-specific characteristics that are influenced by local environmental signals, which impact on their functions during homeostasis, inflammation, and infection. The novel concept is proposed that tissue-derived signals and tissue plasticity can override preestablished developmental programming, thereby redefining developmental trajectories and cDC2 functionality. Ultimately, understanding cDC2 heterogeneity and plasticity has important implications for modulating T cell immunity in health and disease.
Community engagement is essential for shaping equitable biomedical research priorities, but it is often underutilized, especially for marginalized populations. To integrate community feedback from the public into researc...Community engagement is essential for shaping equitable biomedical research priorities, but it is often underutilized, especially for marginalized populations. To integrate community feedback from the public into research, herein we describe a collaborative pilot funded by the Chan Zuckerberg Initiative which pairs the University of California San Francisco (UCSF) with the Rafiki Coalition for Health and Wellness. Utilizing focus groups modeled on Research Prioritization by Affected Communities, participants identified themes that included mistrust in healthcare, representation gaps, and the need for culturally responsive research. Priorities such as mental health, chronic disease, and access to black providers were highlighted. The findings emphasize the need for sustained, grassroots partnerships to drive inclusive research agendas.
Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are frequently associated with immune-related adverse events (irAEs). This article offers a novel synthesis of findings from both preclinical and...Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are frequently associated with immune-related adverse events (irAEs). This article offers a novel synthesis of findings from both preclinical and clinical studies, focusing on the molecular mechanisms driving irAEs across diverse organ systems. It examines key immune cells, such as T cell subsets and myeloid cells, which are instrumental in irAE pathogenesis, alongside an in-depth analysis of cytokine signaling [interleukin (IL)-6, IL-17, IL-4), interferon γ (IFN-γ), IL-1β, tumor necrosis factor α (TNF-α)], integrin-mediated interactions [integrin subunits αITGA)4 and ITGB7], and microbiome-related factors that contribute to irAE pathology. This exploration of modifiable pathways uncovers new opportunities to mitigate irAEs by using available antibodies (Abs) that target key inflammatory molecules across tumor types, while ideally preserving the antitumor efficacy of ICIs.
Diverse macrophage populations inhabit the rodent and human central nervous system (CNS), including microglia in the parenchyma and border-associated macrophages (BAMs) in the meninges, choroid plexus, and perivascular s...Diverse macrophage populations inhabit the rodent and human central nervous system (CNS), including microglia in the parenchyma and border-associated macrophages (BAMs) in the meninges, choroid plexus, and perivascular spaces. These innate immune phagocytes are essential in brain development and maintaining homeostasis, but they also play diverse roles in neurological diseases. In this review, we highlight the emerging roles of CNS macrophages in regulating vascular function in health and disease. We discuss that, in addition to microglia, BAMs, including perivascular macrophages, play roles in supporting vascular integrity and maintaining blood flow. We highlight recent advancements in understanding how these macrophages are implicated in protecting against vascular dysfunction and modulating the progression of cerebrovascular diseases, as seen in vessel-associated neurodegeneration.
Generalized pustular psoriasis (GPP) is a rare human autoinflammatory disorder with life-threatening systemic effects. Keratinocyte-derived interleukin (IL)-36 signaling has been identified as a key mediator of immune re...Generalized pustular psoriasis (GPP) is a rare human autoinflammatory disorder with life-threatening systemic effects. Keratinocyte-derived interleukin (IL)-36 signaling has been identified as a key mediator of immune response in the skin of affected individuals. Recognition of various mutations along the IL-36 axis and the downstream nuclear transcription factor κB (NF-κB) signaling have established GPP as genetically, immunologically, and histopathologically distinct and amenable to immunomodulation, which is epitomized by the recent success of IL-36 antagonism. This review covers recent discoveries of the genetic and immunological underpinnings of GPP, which have proved fertile ground for improving the quality of care of this clinically challenging and debilitating condition.
Tumor-initiating cells (TICs) are particularly efficient at evading detection and elimination by the human immune system. Recent data from Yang and collaborators demonstrate that - at least in preclinical hepatocellular...Tumor-initiating cells (TICs) are particularly efficient at evading detection and elimination by the human immune system. Recent data from Yang and collaborators demonstrate that - at least in preclinical hepatocellular carcinoma models - the immunological privilege of CD49f TICs can be limited by targeting CD155, resulting in restored sensitivity to immune checkpoint inhibitors.
When B cells engage in an immune response, metabolic reprogramming is key to meeting cellular energetic and biosynthetic demands. Epstein-Barr virus (EBV) is a highly prevalent gamma-herpesvirus, latently infecting B cel...When B cells engage in an immune response, metabolic reprogramming is key to meeting cellular energetic and biosynthetic demands. Epstein-Barr virus (EBV) is a highly prevalent gamma-herpesvirus, latently infecting B cells for the human host's lifetime. By hijacking signaling pathways of T cell-dependent humoral immunity, EBV activates B cells in a T cell-independent manner, forcing lymphoblastoid transformation. Interlinked with this coercion of signaling pathways, EBV has also evolved strategies to manipulate B cell metabolism. In this opinion article we integrate recent findings from studies of B cell metabolic reprogramming after EBV infection and during antigen-specific activation, respectively. We hypothesize that defining EBV host-cell metabolic vulnerabilities that differ from pathways required for B cell immunity might uncover novel therapeutic targets against EBV-related diseases.
Laboratory mice housed under specific pathogen-free (SPF) conditions are the standard model in biomedical research. However, experiments with a particular inbred mouse strain performed in different laboratories often yie...Laboratory mice housed under specific pathogen-free (SPF) conditions are the standard model in biomedical research. However, experiments with a particular inbred mouse strain performed in different laboratories often yield inconsistent or conflicting data due to housing-specific variations in the composition and diversity of SPF microbiota. These variations affect immune and nonimmune cell functions, leading to systemic physiological changes. Consequently, microbiota-dependent inconsistencies have raised general doubts regarding the suitability of mice as model organisms. Since stability positively correlates with biological diversity, we postulate that increasing species diversity can improve microbiota stability and mouse physiology, enhancing robustness, reproducibility, and experimental validity. Similar to the generation of inbred mouse strains in the last century, we suggest a worldwide initiative to define a transplantable 'wild' microbiota that stably colonizes mice irrespective of housing conditions.
Biomolecular condensates are membraneless organelles formed through liquid-liquid phase separation. Innate immunity is essential to host defense against infections, but pathogens also harbor sophisticated mechanisms to e...Biomolecular condensates are membraneless organelles formed through liquid-liquid phase separation. Innate immunity is essential to host defense against infections, but pathogens also harbor sophisticated mechanisms to evade host defense. The formation of biomolecular condensates emerges as a key biophysical mechanism in host-pathogen interactions, playing pivotal roles in regulating immune responses and pathogen life cycles within the host. In this review we summarize recent advances in our understanding of how biomolecular condensates remodel membrane-bound organelles, influence infection-induced cell death, and are hijacked by pathogens for survival, as well as how they modulate mammalian innate immunity. We discuss the implications of dysregulated formation of biomolecular condensates during host-pathogen interactions and infectious diseases and propose future directions for developing potential treatments against such infections.
Gopee and colleagues' recent analyses of diverse high-dimensional datasets of prenatal and adult skin, together with data from complex skin organoids, uncover the important contributions of macrophages in modulating pren...Gopee and colleagues' recent analyses of diverse high-dimensional datasets of prenatal and adult skin, together with data from complex skin organoids, uncover the important contributions of macrophages in modulating prenatal skin development, scarless wound healing, and angiogenesis. These findings identify a role for skin immune cells in tissue development.
Trends Immunol
· 2024 Dec · PMID 39603891
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In the battle against cancer, researchers are exploring the use of engineered bacteria as living medicines. Redenti and colleagues demonstrate that Escherichia coli Nissle 1917 (EcN) can be engineered to deliver cancer n...In the battle against cancer, researchers are exploring the use of engineered bacteria as living medicines. Redenti and colleagues demonstrate that Escherichia coli Nissle 1917 (EcN) can be engineered to deliver cancer neoantigen payloads, stimulating antigen-specific CD4 and CD8 T cells and mediating antitumor immunity in preclinical models of colorectal cancer and melanoma.
The recent discovery by Lu and colleagues of Tomasiella immunophila, a bacterium that degrades IgA, offers insights into microbial influences on mucosal immunity and evolutionary immune trade-offs. By modulating IgA tite...The recent discovery by Lu and colleagues of Tomasiella immunophila, a bacterium that degrades IgA, offers insights into microbial influences on mucosal immunity and evolutionary immune trade-offs. By modulating IgA titers, T. immunophila influences the dynamic interactions and balance between the host and pathogen. This has implications for immune health, microbiome research, and therapeutics.
The polycomb repressive complex 2 (PRC2) is an established therapeutic target in cancer. PRC2 catalyzes methylation of histone H3 at lysine 27 (H3K27me3) and is known for maintaining eukaryote cell identity. Recent disco...The polycomb repressive complex 2 (PRC2) is an established therapeutic target in cancer. PRC2 catalyzes methylation of histone H3 at lysine 27 (H3K27me3) and is known for maintaining eukaryote cell identity. Recent discoveries show that modulation of PRC2 not only impacts cell differentiation and tumor growth but also has immunomodulatory properties. Here, we integrate multiple immunological fields to understand PRC2 and its subunits in epigenetic canonical regulation and non-canonical mechanisms within innate immunity. We discuss how PRC2 regulates hematopoietic stem cell proliferation, myeloid cell differentiation, and shapes innate immune responses. The PRC2 catalytic domain EZH2 is upregulated in various human inflammatory diseases and its deletion or inhibition in experimental mouse models can reduce disease severity, emphasizing its importance in regulating inflammation.
Chronic antigen exposure is frequently associated with T cell exhaustion. In a recent study, Aljobaily et al. show that pancreatic islet-infiltrating CD4 T cells in mouse autoimmune diabetes may circumvent exhaustion by...Chronic antigen exposure is frequently associated with T cell exhaustion. In a recent study, Aljobaily et al. show that pancreatic islet-infiltrating CD4 T cells in mouse autoimmune diabetes may circumvent exhaustion by preserving TCF1 expression. Continuous recruitment of epigenetically pre-programmed CD62L CD4 T cells seems to sustain the local autoimmune response.
Innate immune cells that are epigenetically reprogrammed by infection can modify host responses to subsequent infections. Lercher et al. have identified epigenetic reprogramming of murine airway-resident macrophages foll...Innate immune cells that are epigenetically reprogrammed by infection can modify host responses to subsequent infections. Lercher et al. have identified epigenetic reprogramming of murine airway-resident macrophages following recovery from SARS-CoV-2 infection, conferring protection from pathology and lethality following secondary influenza A virus (IAV) challenge without reducing viral titers.