Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of death worldwide. TB pathogenesis is shaped by a complex interaction between the pathogen and host immune responses, part...Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of death worldwide. TB pathogenesis is shaped by a complex interaction between the pathogen and host immune responses, particularly through mechanisms such as oxidative stress and ferroptosis; a form of regulated necrotic cell death driven by iron-dependent lipid peroxidation. This Review highlights recent insights into how Mtb modulates oxidative stress pathways and thus triggers ferroptosis in host cells. Understanding the interplay between oxidative stress responses and cellular and tissue necrosis opens new avenues for therapeutic interventions of TB by controlling bacterial growth and preventing host tissue damage.
Various mammalian CD8 T cell subsets with regulatory properties are either formed through a thymus-dependent mechanism or induced under various experimental protocols and referred to as CD8 regulatory T cells (Tregs). CD...Various mammalian CD8 T cell subsets with regulatory properties are either formed through a thymus-dependent mechanism or induced under various experimental protocols and referred to as CD8 regulatory T cells (Tregs). CD8 Tregs maintain distinct functions in the presence of CD4 Tregs. This review focuses on the Foxp3CD8 Treg subset, which is typically extremely rare in unmanipulated mice and healthy humans under steady-state conditions. However, they can be induced and expanded for transplantation, autoimmune diseases, cancer, viral infections, and T cell receptor transgenic adoptive cell transfer models. Here, we summarize recent research progress related to this population, including the identification of phenotypic markers, induction determinants, and functional activities. Additionally, we discuss advances in manipulating Foxp3CD8 Tregs in autoimmunity and transplantation.
The devastating impact of respiratory infections demonstrates the critical need for novel prophylactic vaccines. In this opinion article, we advocate for bacterial immunotherapies as a complementary tool in our fight aga...The devastating impact of respiratory infections demonstrates the critical need for novel prophylactic vaccines. In this opinion article, we advocate for bacterial immunotherapies as a complementary tool in our fight against respiratory infections. These immunotherapies can activate a wide spectrum of immunological mechanisms, with trained immunity (TI) being particularly significant. This phenomenon has led to the concept of trained immunity-based vaccines (TIbVs), which represent a novel approach in vaccinology. We discuss examples of TIbVs, including the tuberculosis vaccine Bacille Calmette-Guérin (BCG) and the polybacterial immunotherapy MV130. From our viewpoint, illustrating the mode of action and clinical evidence supports the proposal that TIbVs should be considered as next-generation vaccines to confer protection against a wide range of respiratory infections.
Trends Immunol
· 2025 Apr · PMID 40113535
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Microglia, key orchestrators of the brain's immune responses, play a pivotal role in the progression of Alzheimer's disease (AD). Emerging human models, including stem cell-derived microglia and cerebral organoids, are t...Microglia, key orchestrators of the brain's immune responses, play a pivotal role in the progression of Alzheimer's disease (AD). Emerging human models, including stem cell-derived microglia and cerebral organoids, are transforming our understanding of microglial contributions to AD pathology. In this review, we highlight how these models have uncovered human-specific microglial responses to amyloid plaques and their regulation of neuroinflammation, which are not recapitulated in animal models. We also illustrate how advanced human models that better mimic brain physiology and AD pathology are providing unprecedented insights into the multifaceted roles of microglia. These innovative approaches, combined with sophisticated technologies for cell editing and analysis, are shaping AD research and opening new avenues for therapeutic interventions targeting microglia.
IFN-γ is a pleiotropic antiviral cytokine that coordinates innate and adaptive immune responses and induces both immunostimulatory and immunosuppressive activities, limiting its use in the clinic. Due to its antiviral ro...IFN-γ is a pleiotropic antiviral cytokine that coordinates innate and adaptive immune responses and induces both immunostimulatory and immunosuppressive activities, limiting its use in the clinic. Due to its antiviral role, several viruses express proteins that bind IFN-γ, blocking its interaction with the IFN-γ receptor (IFNGR). However, varicella zoster virus glycoprotein C binds IFN-γ and induces the expression of a subset of specific ISGs, similar to biased IFN-γ agonists generated based on the crystal structure of the IFN-γ - IFNGR complex. Here, we propose using structural and mechanistic information from viral proteins and biased agonists to design novel IFN-γ agonists that fine-tune IFN-γ - IFNGR activity, reducing the immunosuppressive and toxic effects of this cytokine.
Patients with an inborn error of immunity (IEI) often show a complete penetrance of their disease-causing mutation, whereas other forms of IEI show a family pattern where many family members carrying the same mutation re...Patients with an inborn error of immunity (IEI) often show a complete penetrance of their disease-causing mutation, whereas other forms of IEI show a family pattern where many family members carrying the same mutation remain unaffected. The underlying mechanism, differential allele-specific expression, was recently and elegantly demonstrated by Stewart et al.
Arthritis is associated with varying degrees of intestinal inflammation and microbiota dysbiosis, leading to the 'gut-joint axis hypothesis' in which intestinal and joint inflammation are suggested to be interconnected t...Arthritis is associated with varying degrees of intestinal inflammation and microbiota dysbiosis, leading to the 'gut-joint axis hypothesis' in which intestinal and joint inflammation are suggested to be interconnected through immune-microbiota interactions. While clinical observations support this, causality remains uncertain. Rodent models have provided insights into potential mechanisms by uncovering microbial influences and immune pathways that either connect or uncouple gut and joint inflammation. Based on recent findings, we propose the 'immune hypersensitivity hypothesis' whereby central immune hyper-reactivity can independently drive joint inflammation via local sterile triggers, and gut inflammation via microbial triggers. We argue that this suggests a more nuanced role of the microbiota in arthritis pathogenesis that varies according to the predominant immune mechanisms in disease subtypes. We explore gut-immune interactions in arthritis, highlight ongoing challenges, and propose future research directions.
Supporting emerging immunologists in Latin America and the Caribbean (LAC) is crucial amidst fragile funding and policy shifts in the region. Their growth can deliver region-specific health solutions, foster pandemic pre...Supporting emerging immunologists in Latin America and the Caribbean (LAC) is crucial amidst fragile funding and policy shifts in the region. Their growth can deliver region-specific health solutions, foster pandemic preparedness, and advance neglected tropical disease research, paying it forward to reduce health inequities and drive global scientific progress.
The mammalian inflammasome is crucial for responding to environmental/intrinsic stress, and its regulation remains a significant focus in immune-mediated inflammatory diseases and antitumor immunity. Recent studies highl...The mammalian inflammasome is crucial for responding to environmental/intrinsic stress, and its regulation remains a significant focus in immune-mediated inflammatory diseases and antitumor immunity. Recent studies highlight a close link between palmitoylation and inflammasome regulation. However, this type of regulation remains elusive but may harbor potential for combating inflammation-driven disorders.
IFI27, an interferon (IFN)-stimulated gene, is emerging as a crucial player in immune responses across various species, with significant implications for precision medicine. Commonly found among the most upregulated gene...IFI27, an interferon (IFN)-stimulated gene, is emerging as a crucial player in immune responses across various species, with significant implications for precision medicine. Commonly found among the most upregulated genes in infections, cancers, as well as inflammatory and autoimmune disorders, IFI27 is ready to be trialed in clinical practice for certain indications, and holds promise as an immunomodulatory target. We hypothesize that IFI27 plays a dual role, typically supporting immune defense but sometimes contributing to disease progression, which might render it a putative biomarker for diagnosis, prognosis, and treatment response. We advocate for focused research on IFI27 to unlock its potential in precision medicine and to contribute to a unifying framework of its mechanisms in the immune response. Our viewpoint is supported by numerous studies highlighting IFI27's involvement across various conditions and the possibilities for clinical application.
Sleep is a major driver of waste clearance from the brain, but the mechanisms underpinning brain cleansing during sleep, which are also important for immunological functions, are poorly understood. Recent mouse work by H...Sleep is a major driver of waste clearance from the brain, but the mechanisms underpinning brain cleansing during sleep, which are also important for immunological functions, are poorly understood. Recent mouse work by Hauglund et al. shows how oscillatory surges in norepinephrine (NE) during sleep drive vascular pulsation and cerebrospinal fluid (CSF) movement to cleanse the brain.
Lymph node (LN) fibroblastic reticular cells (FRCs) are key regulators of mammalian adaptive immune responses. Together with their deposited extracellular matrix (ECM), FRCs form a reticular network that provides mechani...Lymph node (LN) fibroblastic reticular cells (FRCs) are key regulators of mammalian adaptive immune responses. Together with their deposited extracellular matrix (ECM), FRCs form a reticular network that provides mechanical strength to LNs. Furthermore, the ECM regulates various cell functions including proliferation and differentiation. The ECM is dynamically remodeled in activated LNs, thereby affecting immune cell survival and function. Although both the LN ECM and FRCs can affect immune reactivity, a link between altered LN ECM during an immune response and ECM-producing FRCs is lacking. We explore recent work on the complex interplay between FRCs, ECM, and immune cells in health and disease, and provide guidance for future research to understand the complex regulation of the adaptive immune system within LNs.
Trends Immunol
· 2025 Mar · PMID 40016052
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Lytic cell death is crucial for antimicrobial and antitumor immunity; however, unchecked pyroptosis drives pathology in sepsis. Wright et al. demonstrate that widespread cell death following pyroptosis is propagated by e...Lytic cell death is crucial for antimicrobial and antitumor immunity; however, unchecked pyroptosis drives pathology in sepsis. Wright et al. demonstrate that widespread cell death following pyroptosis is propagated by extracellular vesicles (EVs) carrying gasdermin D (GSDMD) pores that become integrated into the membrane of neighboring cells, driving inflammatory cell death.
Helper innate lymphoid cells (ILCs), comprising groups ILC1, ILC2, and ILC3, possess unique advantages in eliciting rapid immune responses and were recently found to exhibit direct tumor-killing capacities comparable wit...Helper innate lymphoid cells (ILCs), comprising groups ILC1, ILC2, and ILC3, possess unique advantages in eliciting rapid immune responses and were recently found to exhibit direct tumor-killing capacities comparable with those of cytotoxic ILCs [natural killer (NK) cells] in humans and mice. Although ILCs are primarily tissue-resident cells, their role in the hematopoietic system is increasingly being recognized. This review provides an overview of ILC ontogeny, as well as the physiological and pathological roles of these cells within the human and murine hematopoietic systems. We recapitulate recent advancements regarding ILC embryonic hematopoietic origin and the dynamic interactions between ILCs and leukemic cells or other immune cell populations, highlighting the dual roles ILCs can play in carcinogenesis. Exploring the functional potential of ILCs can inform the design of rational immunotherapeutic strategies against hematological malignancies.
Trends Immunol
· 2025 Mar · PMID 40011156
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Osteoimmunology is an interdisciplinary branch of immunology studying bidirectional interactions between the immune and skeletal systems. Bone marrow is vital for the production of immune cells and is implicated in multi...Osteoimmunology is an interdisciplinary branch of immunology studying bidirectional interactions between the immune and skeletal systems. Bone marrow is vital for the production of immune cells and is implicated in multiple diseases across all immunology disciplines. Here, we briefly discuss recent progress from the past 5 years in the field and how it impacts our current understanding of health and disease.
Trends Immunol
· 2025 Mar · PMID 39984354
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Fevers are an ancient feature of the inflammatory microenvironment. While fevers may improve the immune response to pathogens, mechanisms are unclear. We explore recent studies of how fever-range temperatures inform mamm...Fevers are an ancient feature of the inflammatory microenvironment. While fevers may improve the immune response to pathogens, mechanisms are unclear. We explore recent studies of how fever-range temperatures inform mammalian T cell metabolism, differentiation, and stress responses. Recent evidence indicates that metabolic programs initiated by fever are maintained upon return to thermo-normality, potentially providing a lasting benefit. Despite its impact, temperature remains overlooked and warrants further study. This is especially apparent when considering the wide temperature differential between tissues within the body and during inflammatory disease progression. We propose that differences in the metabolic and stress responses between T cell subsets upon thermal stress contribute to determining immune cell makeup and fate during inflammation.
Decidual stromal cells (DSCs) are involved in immunoregulatory mechanisms that prevent fetal rejection by the mammalian maternal immune system. Recent studies using single-cell RNA sequencing demonstrated the existence o...Decidual stromal cells (DSCs) are involved in immunoregulatory mechanisms that prevent fetal rejection by the mammalian maternal immune system. Recent studies using single-cell RNA sequencing demonstrated the existence of different types of human and mouse DSCs, highlighting corresponding differentiation (decidualization) pathways, and suggesting their involvement in the immune response during normal and pathological pregnancy. DSCs may be considered tissue-specialized fibroblasts because both DSCs and fibroblasts share phenotypic and functional similarities in immunologically challenged tissues, especially in terms of their immune functions. Indeed, fibroblasts can setup, support, and suppress immune responses and these functions are also performed by DSCs. Moreover, fibroblasts and DSCs can induce ectopic foci as tertiary lymphoid structures (TLSs), and endometriosis, respectively. Thus, understanding DSC immunoregulatory functions is of timely relevance.
The adaptor protein mitochondrial antiviral signaling protein (MAVS)-mediated innate immune response is essential for host defense against RNA viruses. Gokhale and colleagues report that cellular mRNAs assemble and activ...The adaptor protein mitochondrial antiviral signaling protein (MAVS)-mediated innate immune response is essential for host defense against RNA viruses. Gokhale and colleagues report that cellular mRNAs assemble and activate the MAVS signalosome by directly binding to MAVS and regulating its interactors, consequently enhancing antiviral signaling and interferon expression to inhibit viral infection.
Tumor-infiltrating regulatory T (TI-Treg) cells constitute key components within the tumor microenvironment (TME) to suppress antitumor immunity and facilitate tumor progression. Although multiple therapies have been dev...Tumor-infiltrating regulatory T (TI-Treg) cells constitute key components within the tumor microenvironment (TME) to suppress antitumor immunity and facilitate tumor progression. Although multiple therapies have been developed to eliminate TI-Treg cells, most of them exhibit only modest efficacy and harbor risks of inducing immune-related adverse events (irAEs). Recent studies demonstrate that CC chemokine receptor (CCR)8 is highly and specifically expressed on effector TI-Treg cells in mice and humans, highlighting CCR8 as a promising target for selective TI-Treg cell depletion in the treatment of various cancers. Here, we concentrate on the latest understanding of CCR8 regarding its expression, functions, and regulation, and summarize the current landscape of CCR8-targeted therapies. With favorable efficacy and safety, the latter represent an important class of next-generation putative cancer immunotherapies.