Active regulation of T cell quiescence is important to sustain immune responses to vaccination and infection while preventing inappropriate responses such as autoimmunity. Recent studies highlight that quiescence in naïv...Active regulation of T cell quiescence is important to sustain immune responses to vaccination and infection while preventing inappropriate responses such as autoimmunity. Recent studies highlight that quiescence in naïve T cells is actively regulated by transcription factors and tonic signaling. Loss of quiescence in aged T cells has significant consequences because the cells are less responsive to infection or vaccination. This review covers the current state of knowledge about transcriptional regulation of naïve T cell quiescence and how quiescence is lost in aged hosts and during chronic infection. Finally, we discuss the need for a deeper understanding of the factors involved in cell quiescence to identify targets to restore cell quiescence in dysfunctional T cells.
Understanding the mechanisms implicated in the establishment of trained immunity could aid the design of novel therapeutic approaches. By studying Bacille Calmette-Guerin (BCG) vaccination in a human cohort, Ziogas and c...Understanding the mechanisms implicated in the establishment of trained immunity could aid the design of novel therapeutic approaches. By studying Bacille Calmette-Guerin (BCG) vaccination in a human cohort, Ziogas and colleagues demonstrate the role of lactate generation and its use for histone lactylation as a key mechanism for establishing innate immune memory.
Microglia replacement is reshaping neurodegenerative disease therapy, yet its key prerequisites remain unclear. In the current issue of Immunity, Aisenberg et al. and Bastos et al. reveal how developmental origin influen...Microglia replacement is reshaping neurodegenerative disease therapy, yet its key prerequisites remain unclear. In the current issue of Immunity, Aisenberg et al. and Bastos et al. reveal how developmental origin influences monocyte engraftment into the brain, and demonstrate the therapeutic potential of monocyte-based interventions in a monogenic neurological disease.
N-methyladenosine (mA) is a key mRNA modification influencing mRNA stability and translation. YTHDF2, a major mA 'reader', was initially recognized for promoting mRNA decay but is now also known to enhance translation by...N-methyladenosine (mA) is a key mRNA modification influencing mRNA stability and translation. YTHDF2, a major mA 'reader', was initially recognized for promoting mRNA decay but is now also known to enhance translation by binding to methylated mRNAs. YTHDF2 maintains the function of immune suppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), while also supporting cytotoxic immune cells, including natural killer (NK) and CD8 T cells. Additionally, YTHDF2 acts as a tumor-intrinsic regulator orchestrating tumor immune evasion. Its multifaceted roles in tumor immunity make YTHDF2 a promising yet challenging therapeutic target. This review explores the complex roles and mechanisms of YTHDF2 in cancers, immune regulation, and tumor immune evasion and highlights emerging therapeutic strategies that target YTHDF2.
Trends Immunol
· 2025 Jun · PMID 40393889
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Proteins with a Toll/interleukin-1 receptor/resistance (TIR) domain are among the most ancient immune regulators and include well-known pattern recognition receptors (PRRs). A specialized subset of TIR domain proteins ar...Proteins with a Toll/interleukin-1 receptor/resistance (TIR) domain are among the most ancient immune regulators and include well-known pattern recognition receptors (PRRs). A specialized subset of TIR domain proteins are enzymes that predominantly use nicotinamide adenine dinucleotide (NAD) to generate second messenger metabolites. These enzymatic TIR proteins have essential roles in bacteria, plant, and animal immunity. The mechanism of activation of these TIR proteins, conserved across Kingdoms, involves oligomerization into higher-ordered structures, which activates their intrinsic enzymatic activity. Here, we review the functions of enzymatic TIR proteins in innate immunity in bacteria, plants, and animals. This work offers insights into the evolutionary origins of immunity itself and defines fundamental principles of immune surveillance across the Tree of Life.
Although DNA damage is a common cellular event, T cells experience significant genotoxic stresses because of rapid antigen-stimulated expansion and their presence in various nonlymphoid microenvironments. In addition to...Although DNA damage is a common cellular event, T cells experience significant genotoxic stresses because of rapid antigen-stimulated expansion and their presence in various nonlymphoid microenvironments. In addition to the well-established link between genomic instability and malignancy, recent genomic studies have uncovered a substantial mutational burden in nonmalignant T cells in both normal aging and disease contexts. Furthermore, genomic damage in T cells is accelerated in autoimmune diseases and in older individuals because of both intrinsic and extrinsic factors. This review highlights the different genotoxic stressors affecting T cells and the detrimental effects of persistent DNA damage and identifies the most critical knowledge gaps.
Macrophages play a central role in maintaining tissue homeostasis and in surveillance against pathogens and disease. In the lung, they can adopt either proinflammatory or anti-inflammatory states depending on the nature...Macrophages play a central role in maintaining tissue homeostasis and in surveillance against pathogens and disease. In the lung, they can adopt either proinflammatory or anti-inflammatory states depending on the nature of the stimulus. As the predominant immune cells in both the lung tumor microenvironment and in sites of lung infection, the functional plasticity of macrophages makes them key players in determining disease outcome. Accurately defining their inflammatory profiles offers an opportunity to reprogram infection-associated macrophages towards enhanced tumor-killing phenotypes. This review explores how acute inflammation can drive macrophage-mediated antitumor immunity and highlights key molecules and signaling pathways that may be leveraged to therapeutically modulate macrophage function.
Recently, Kondo et al. engineered the coexpression of a T cell receptor (TCR) and a chimeric antigen receptor (CAR) and developed an antagonism-enforced braking system where TCR signals both enhance and inhibit CAR activ...Recently, Kondo et al. engineered the coexpression of a T cell receptor (TCR) and a chimeric antigen receptor (CAR) and developed an antagonism-enforced braking system where TCR signals both enhance and inhibit CAR activation. This work may enable rational design of CAR-T agents that limit toxicity to healthy tissue.
Emerging studies demonstrate the presence of cells with microglial features in peripheral tissues. Here, we propose using the term 'microglial lineage' to categorize both these cells and classical microglia. Microglial l...Emerging studies demonstrate the presence of cells with microglial features in peripheral tissues. Here, we propose using the term 'microglial lineage' to categorize both these cells and classical microglia. Microglial lineage cells are resident immune cells with a microglial molecular phenotype and ontogeny that exhibit diverse tissue distribution and functions.
Trends Immunol
· 2025 Jun · PMID 40340168
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The upsurge of mpox (formerly known as monkeypox) in Africa and its global spread highlight the need for improved vaccines. The development of new recombinant vaccines, including mRNA and protein nanoparticles, depends o...The upsurge of mpox (formerly known as monkeypox) in Africa and its global spread highlight the need for improved vaccines. The development of new recombinant vaccines, including mRNA and protein nanoparticles, depends on understanding the biology of poxviruses and selecting the most protective immunogens. Animal studies demonstrate that vaccines need to target the antigens of both infectious forms - the mature virion and the enveloped virion - which display surface proteins responsible for cell entry and cell-to-cell spread, respectively. Although some of these proteins have been shown to induce protective antibodies, others including most of those that are essential for membrane fusion remain to be tested. We review the structures of orthopoxvirus surface proteins as a guide to the selection of optimal antigens for recombinant vaccines.
Brook B, Goetz M, Duval V
… +2 more, Micol R, Dowling DJ
Trends Immunol
· 2025 May · PMID 40268657
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The development of ionizable mRNA-lipid nanoparticle (mRNA-LNP) nucleic acid carriers facilitated the clinical translation of the Coronavirus 2019 (COVID-19) mRNA vaccines BNT162b2 and mRNA-1273. Here, we discuss insight...The development of ionizable mRNA-lipid nanoparticle (mRNA-LNP) nucleic acid carriers facilitated the clinical translation of the Coronavirus 2019 (COVID-19) mRNA vaccines BNT162b2 and mRNA-1273. Here, we discuss insights into rational improvements to mRNA vaccines, focusing on LNP modifications for mRNA-LNP biodistribution control, miRNA-based biodistribution control of encoded transcripts, and precision adjuvantation strategies.
Inflammasomes form in response to infection, cellular stress, or damage. Gain-of-function (GOF) mutations in inflammasome receptors have been identified as the underlying cause of severe inflammatory diseases, termed 'in...Inflammasomes form in response to infection, cellular stress, or damage. Gain-of-function (GOF) mutations in inflammasome receptors have been identified as the underlying cause of severe inflammatory diseases, termed 'inflammasomopathies'. Recently, molecular interrogation of these diseases revealed several distinctions at the level of the tissue affected, the inflammatory mediators that drive disease progression, and the contribution of programmed cell death. In this review we discuss key emerging differences across inflammasomopathies and the distinct inflammatory patterns seen in patients. We discuss how programmed cell death influences the progression of inflammasomopathies and the role of plasma membrane rupture. Understanding the molecular disease signatures across inflammasomopathies provides crucial insights into identifying and treating the underlying disease and opens new avenues for therapeutic interventions.
Nixon DF, Bachtel ND, Hupert N
… +1 more, Eleftherianos I
Trends Immunol
· 2025 May · PMID 40251093
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A genealogy of immunity reveals increasingly complex systems for pathogen response, organism homeostasis, and multispecies interaction. New studies show how the five senses can all contribute to behavioral, shared and po...A genealogy of immunity reveals increasingly complex systems for pathogen response, organism homeostasis, and multispecies interaction. New studies show how the five senses can all contribute to behavioral, shared and population level immunity redefining our understanding of the ways organisms communicate among and defend themselves.
Epstein-Barr virus (EBV) was the first DNA virus identified to be tightly associated with multiple human tumors. It promotes malignant progression of tumors - including related lymphomas, nasopharyngeal carcinoma, and ga...Epstein-Barr virus (EBV) was the first DNA virus identified to be tightly associated with multiple human tumors. It promotes malignant progression of tumors - including related lymphomas, nasopharyngeal carcinoma, and gastric adenocarcinoma - in part by evading surveillance and attack by the host immune system. In this article we review the main molecular mechanisms by which EBV-encoded proteins and RNAs interact with key molecules of the host immune system to inhibit Toll-like receptor (TLR)-nuclear factor κB (NF-κB), retinoic acid-inducible gene I (RIG-I), and interferon (IFN) signaling pathways, affect antigen presentation, prevent the cytotoxic effects of CD8 effector cells, regulate the tumor microenvironment (TME) and cell metastasis and invasion, and inhibit cell apoptosis. These interactions not only contribute to the persistence of the virus but also provide potential targets for developing new immunotherapy strategies.
Trends Immunol
· 2025 May · PMID 40240192
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The Molecular Mechanisms of Immune Cell Development and Function (MMICDF) meeting sponsored by the Federation of American Societies of Experimental Biology (FASEB) occupies a special niche because of its focus on the mol...The Molecular Mechanisms of Immune Cell Development and Function (MMICDF) meeting sponsored by the Federation of American Societies of Experimental Biology (FASEB) occupies a special niche because of its focus on the molecular mechanisms that underpin immunological processes. This biennial meeting with small groupings of participants and interactive nature has provided a forum for intense, informative, and influential scientific discussions. The meeting is unique for its focus on molecular mechanisms that control the exceptional processes of DNA recombination, somatic hypermutation (SHM), and gene expression during immune cell development, activation, and differentiation. The organizers of the foundational meeting reflect on the coalescence of scientific advances that catalyzed its origin, review meeting highlights to celebrate its 20th anniversary, and project into the future.
Vaccination campaigns have reshaped infectious disease dynamics, exerting selective pressures on pathogens. While some are controlled, others persist via antigenic variation or reservoirs. This Science & Society explores...Vaccination campaigns have reshaped infectious disease dynamics, exerting selective pressures on pathogens. While some are controlled, others persist via antigenic variation or reservoirs. This Science & Society explores the evolutionary and ecological impacts of vaccination, highlighting its role in pathogen adaptation and implications for future disease control strategies.
In the germinal center (GC), B cells undergo rounds of somatic hypermutation (SHM), proliferation, and positive selection to develop into high-affinity, long-lived plasma cells and memory B cells. It is well established...In the germinal center (GC), B cells undergo rounds of somatic hypermutation (SHM), proliferation, and positive selection to develop into high-affinity, long-lived plasma cells and memory B cells. It is well established that, upon activation, B cells significantly alter their metabolism, but until recently little was understood about their metabolism within the GC. In this review we discuss novel in vivo models in which GC B cell (GCBC) metabolism is disrupted; these have greatly increased our understanding of B cell metabolic phenotype. GCBCs are unusual in that, unlike almost all other rapidly proliferating immune cells, they use little glycolysis but prefer fatty acid oxidation (FAO) to fuel ATP synthesis, whilst preferentially utilizing glucose and amino acids as carbon and nitrogen sources for biosynthetic pathways.
While highlighting the complexity and heterogeneity of tumor immune microenvironments, the application of single-cell analyses in human cancers has identified recurrent subsets of tumor-associated macrophages (TAMs). Amo...While highlighting the complexity and heterogeneity of tumor immune microenvironments, the application of single-cell analyses in human cancers has identified recurrent subsets of tumor-associated macrophages (TAMs). Among these, interleukin (IL)-1β TAMs - cells with high levels of expression of inflammatory response and tissue repair genes, but with limited capacity to stimulate cytotoxic immunity - are emerging as key drivers of pathogenic inflammation in cancer. In this review we discuss recent literature defining the phenotypical, molecular, and functional properties of IL-1β TAMs, as well as their temporal dynamics and spatial organization. Elucidating the biology of these cells across tumor initiation, progression, metastasis, and therapy could inform the design and interpretation of clinical trials targeting IL-1β and/or other inflammatory factors in cancer immunotherapy.
The ongoing evolution of SARS-CoV-2 poses significant challenges to existing neutralizing antibodies and vaccines through immune escape mutations. By leveraging genomic surveillance and antibody deep mutational scanning...The ongoing evolution of SARS-CoV-2 poses significant challenges to existing neutralizing antibodies and vaccines through immune escape mutations. By leveraging genomic surveillance and antibody deep mutational scanning (DMS) data, Raharinirina and colleagues developed a computational framework to elucidate region-specific SARS-CoV-2 variant dynamics and predict evolutionary trends under population immunity.
Cancer is increasingly prevalent worldwide, often coexisting with type 2 diabetes (T2D). Recent breakthroughs reveal the immune system's pivotal role in eliminating tumors and how the metabolic environment, such as gluco...Cancer is increasingly prevalent worldwide, often coexisting with type 2 diabetes (T2D). Recent breakthroughs reveal the immune system's pivotal role in eliminating tumors and how the metabolic environment, such as glucose availability, affects antitumor immunity. Diabetes is known to dysregulate both innate and adaptive immune responses, while cancer creates an immunosuppressive microenvironment. We hypothesize that diabetes in cancer subjects may exacerbate this immunosuppression. Here, we examine the current understanding of the interplay between T2D and solid tumors and the associated challenges. Despite inconsistencies in data from mouse models and human tissues, evidence suggests that T2D can impact the antitumor response. Possible mechanisms may involve myeloid cells, inducing local immunosuppression and impairing antigen presentation, and certain lymphoid cell populations, exhibiting exhaustion.