THEMIS (thymocyte-expressed molecule involved in selection) is the founding member of a family of metazoan proteins distinguished by the presence of a novel structural element designated the cysteine-containing all-beta-...THEMIS (thymocyte-expressed molecule involved in selection) is the founding member of a family of metazoan proteins distinguished by the presence of a novel structural element designated the cysteine-containing all-beta-in-THEMIS (CABIT) module. Several studies have confirmed a critical role for THEMIS in T cell antigen receptor (TCR) signaling during T cell development, and more recent work has shown an important role for THEMIS in peripheral T cells. However, the molecular function of THEMIS in the TCR signaling pathway has long remained controversial due to conflicting experimental results. In this review article, we summarize recent data that provide new insights into the structure, evolution, and broader roles of the CABIT module, as well as clarify the molecular mechanism by which THEMIS influences TCR and cytokine receptor signaling in developing and mature T cells.
Endothelial cells (ECs), which form the monolayer lining the vasculature, serve as critical gatekeepers of vascular homeostasis. They actively coordinate immune cell recruitment, adhesion, migration, and activation. Thro...Endothelial cells (ECs), which form the monolayer lining the vasculature, serve as critical gatekeepers of vascular homeostasis. They actively coordinate immune cell recruitment, adhesion, migration, and activation. Through tightly controlled expression and secretion of chemokines, cytokines, adhesion molecules, and immunomodulatory proteins, ECs locally orchestrate immune responses. In atherosclerosis, ECs contribute to plaque formation, plaque instability, and local inflammation by facilitating immune cell activation and transmigration into the plaque. However, ECs are highly heterogeneous, with their phenotype and function influenced by vascular localization and disease stage. EC subpopulations are transcriptionally distinct and adopt to either proinflammatory or angiogenic phenotypes and differentially participate in immune modulation. This review discusses recent insights into the immunomodulatory functions of ECs in atherosclerosis and underscores the importance of EC heterogeneity in understanding endothelial-immune cell interactions.
Trends Immunol
· 2026 Jun · PMID 41904049
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Natural killer (NK) cells are innate lymphocytes uniquely equipped with stochastically expressed activating and inhibitory receptors that shape their cytotoxic potential. Although traditionally viewed as rapid and potent...Natural killer (NK) cells are innate lymphocytes uniquely equipped with stochastically expressed activating and inhibitory receptors that shape their cytotoxic potential. Although traditionally viewed as rapid and potent innate effectors against infected or transformed cells, we now appreciate that NK cells possess adaptive capabilities, such as antigen-specific clonal expansion and the generation of long-lived memory cells. The ability of NK cells to engage in innate and adaptive immune responses is tightly coordinated by a 'three-signal' framework that relies on the synergy between NK cell receptor engagement (signal 1), co-stimulation (signal 2), and cytokine-mediated signals (signal 3). This review focuses on knowledge gleaned from emerging molecular pathways aimed at modulating signals 1, 2, and 3 to reprogram NK cells for therapeutic utility.
Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a large family of intracellular pattern recognition receptors primarily involved in innate immunity. Although canonical inflammasome-forming NLRs,...Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a large family of intracellular pattern recognition receptors primarily involved in innate immunity. Although canonical inflammasome-forming NLRs, such as NLRP3 and NLRC4, and microbial sensors, including NOD1 and NOD2, are well-characterized, the functions of many other NLRs remain poorly understood. This review article addresses this gap by highlighting the critical, context-dependent roles of these less-characterized NLRs beyond pathogen sensing. We classify these NLRs as immune modulators, regulators of autophagy and mitophagy, tissue-specific effectors, and reproductive mediators, expanding the traditional view of NLR functions. Understanding the diverse, context-dependent roles of NLRs across biological systems is essential to fully understand their complex regulatory networks and therapeutic potential, which extends beyond classical inflammasome functions.
The importance of γδ T cells in cancer, as defenders against tumorigenesis, was established more than 2 decades ago. Since that time, research using mouse models of cancer has brought to light a nonuniform view of tumor-...The importance of γδ T cells in cancer, as defenders against tumorigenesis, was established more than 2 decades ago. Since that time, research using mouse models of cancer has brought to light a nonuniform view of tumor-associated γδ T cells by providing granularity into the role of individual γδ T cell subsets in specific cancer types. In this review, we discuss data that highlight the unique contributions of Vγ1, Vγ4, Vγ5, Vγ6, and Vγ7 cells throughout cancer progression. We delve into their responses to tumors, including both protective and pathogenic functions. We examine how the mechanisms by which these mouse immune cell subsets shape tumor development and spread can be exploited for therapeutic purposes in people with cancer.
Endometriosis is increasingly recognized as a systemic disorder involving complex interactions between nerves and immune cells, driving chronic pain and inflammation beyond the initial theories. Recent breakthroughs high...Endometriosis is increasingly recognized as a systemic disorder involving complex interactions between nerves and immune cells, driving chronic pain and inflammation beyond the initial theories. Recent breakthroughs highlight aberrant sensory nerve growth and dysfunctional immune responses as key events in lesion development and sustained pain. This review systematically examines the functional link between neuroimmune interplay and endometriosis, showing how reciprocal signaling between nerves and immune cells actively shapes epithelial and stromal behavior, amplifies inflammation, and reinforces pain circuitry. Recognizing this integrated neuroimmune framework reframes endometriosis as a disorder of distributed network dysregulation and highlights that targeting key neuroimmune nodes may offer new therapeutic opportunities to curb both lesion progression and endometriosis-related chronic pain.
Group 3 innate lymphoid cells (ILC3s) promote gastrointestinal health, dynamically interface with diet and microbes, and become impaired during chronic inflammation or metabolic syndrome. Torrico and colleagues uncover a...Group 3 innate lymphoid cells (ILC3s) promote gastrointestinal health, dynamically interface with diet and microbes, and become impaired during chronic inflammation or metabolic syndrome. Torrico and colleagues uncover a key pathway rapidly disrupting ILC3 homeostasis in the intestines of humans and mice following the consumption of a high-fat diet.
Adjuvants are critical to improving the magnitude, breadth, functionality, and durability of vaccine immunogenicity. Despite advances in vaccinology, long-term immunity, variant cross-protection, and robust mucosal respo...Adjuvants are critical to improving the magnitude, breadth, functionality, and durability of vaccine immunogenicity. Despite advances in vaccinology, long-term immunity, variant cross-protection, and robust mucosal responses remain unmet goals. These challenges underscore the need for novel, safe, and effective adjuvants. This review explores emerging adjuvants targeting specific immune pathways. We highlight clinical and preclinical studies focusing on adjuvants that enhance durable and persistent humoral, cellular, and mucosal immunity. Current trends are discussed alongside tailored approaches for children and the elderly. Finally, the aim of this review is to highlight novel vaccine adjuvants currently in preclinical and clinical development, with the potential to generate a vaccine platform fit for the necessary yet unmet needs of public health in a postpandemic era.
While artificial intelligence (AI) is transforming biological science, its full potential in immunology has yet to be realized due to limited data and the need for extensive experimental validation. This review provides...While artificial intelligence (AI) is transforming biological science, its full potential in immunology has yet to be realized due to limited data and the need for extensive experimental validation. This review provides a practical guide for experimental immunologists to actively contribute to AI development, with a focus on applications for B- and T-cell receptors. It not only gives an overview of common AI techniques in immunology but also highlights the important role of high-throughput experimental methodologies. Overall, we believe that the synergy between AI and experimental innovation will be a crucial catalyst for advancing the field of immunology.
Deciphering how mRNA vaccines generate humoral immunity could accelerate next-generation vaccine design. Castaño et al. reveal that mRNA-lipid nanoparticle vaccines employ a dual-adjuvant mechanism: nucleoside-modified m...Deciphering how mRNA vaccines generate humoral immunity could accelerate next-generation vaccine design. Castaño et al. reveal that mRNA-lipid nanoparticle vaccines employ a dual-adjuvant mechanism: nucleoside-modified mRNA triggers type I interferons to mature dendritic cells, while lipid nanoparticles induce a pro-T follicular helper cell program, together promoting robust germinal center responses.
Type 2 immunity protects against helminths and venoms, yet its dysregulation drives allergic diseases. Initiation occurs at barrier tissues, where epithelial cells detect perturbations and release alarmins, activating ty...Type 2 immunity protects against helminths and venoms, yet its dysregulation drives allergic diseases. Initiation occurs at barrier tissues, where epithelial cells detect perturbations and release alarmins, activating type 2 innate lymphoid cells and conditioning dendritic cells for T helper 2 priming. However, the framework of type 2 innate immune sensing remains largely incomplete. Critical gaps include the core immunostimulatory components of many stimuli and their host detection pathways. Recent advances, including tuft cell chemosensation, membrane pore formation as a common trigger, and the role of protein crystals and proteases in allergic inflammation, highlight emerging molecular principles. Unlike bacterial, viral, and fungal recognition via conserved molecular patterns, type 2 immunity often involves the sensing of perturbations and stress signals.
The immunological synapse (IS) formed between cytotoxic CD8 T lymphocytes (CTLs) and tumor cells represents the critical interface where many immunotherapies act, including therapeutic antibodies and chimeric antigen rec...The immunological synapse (IS) formed between cytotoxic CD8 T lymphocytes (CTLs) and tumor cells represents the critical interface where many immunotherapies act, including therapeutic antibodies and chimeric antigen receptor immunotherapy. However, detailed characterization of the CTL-tumor IS has remained limited, primarily due to the transient and dynamic nature of this structure. Recent advances in proteomics, transcriptomics, high-throughput imaging, and machine learning are now enabling more precise investigation of this complex cell-cell interaction. This review highlights how emerging technologies have advanced our understanding of the CTL-tumor IS, outlines their potential to inform next-generation immunotherapies, and proposes future directions for technological innovation.
Cheng et al.'s recent study identifies the Cullin3-RING E3 ubiquitin ligase complexes (CRL3) adaptor protein Kelch-like protein 6 (KLHL6) as a proteostasis regulator whose downregulation in chronically stimulated T cells...Cheng et al.'s recent study identifies the Cullin3-RING E3 ubiquitin ligase complexes (CRL3) adaptor protein Kelch-like protein 6 (KLHL6) as a proteostasis regulator whose downregulation in chronically stimulated T cells leads to the accumulation of thymocyte selection-associated high mobility group box protein and phosphoglycerate mutase family member 5, driving T-cell dysfunction. This work positions T-cell exhaustion as a proteostatic disorder and highlights KLHL6 as a promising target for cancer immunotherapy.
IgE contributes to allergy, but its cellular sources are rare and hard to identify. Genetic fate mapping and single-cell sequencing approaches have now revealed that two cell populations maintain IgE: long-lived IgE plas...IgE contributes to allergy, but its cellular sources are rare and hard to identify. Genetic fate mapping and single-cell sequencing approaches have now revealed that two cell populations maintain IgE: long-lived IgE plasma cells (PCs) and 'type 2' memory B cells. This forum piece discusses recent discoveries on long-lived IgE PCs.
Psoriatic arthritis (PsA) is a chronic inflammatory disease that primarily affects the skin, joints, and entheses. Growing evidence implicates alterations at the gut and skin barriers in PsA pathogenesis. These sites pla...Psoriatic arthritis (PsA) is a chronic inflammatory disease that primarily affects the skin, joints, and entheses. Growing evidence implicates alterations at the gut and skin barriers in PsA pathogenesis. These sites play a crucial role in tissue homeostasis, and their disruption can contribute to the translocation of immune cells and bacterial products, resulting in systemic inflammation. Crosstalk between barrier sites and joints can promote or exacerbate disease development, with barriers also being a potential target of disease. This review article provides a barrier-centered perspective across gut, skin, and synovium, with a specific focus on new concepts about intertissue communication involving immune and microbial mediators that can propagate inflammation in PsA.
The rapid development of allogeneic engineered therapeutic cells has intensified the challenge of host immune-mediated rejection. Advances in molecular immunology, genetic engineering, and induced pluripotent stem cell-b...The rapid development of allogeneic engineered therapeutic cells has intensified the challenge of host immune-mediated rejection. Advances in molecular immunology, genetic engineering, and induced pluripotent stem cell-based multigene editing have enabled the creation of 'stealth' allogeneic cells designed to evade immune detection while maintaining function. Key strategies include the deletion of human leukocyte antigen class I and class II molecules to limit T cell recognition, the expression of natural killer (NK) cell inhibitory ligands to prevent NK cell-mediated killing, and the upregulation of CD47 to suppress phagocytosis. An expanding repertoire of immune-modulatory molecules, receptor-ligand interactions, and experimental assays is refining these approaches. Together, stealth designs are accelerating the translation of allogeneic cell therapies toward more durable and broadly applicable clinical use.
Li et al. described a tumor-derived neuroimmune mechanism that promotes clearance of established amyloid pathology in Alzheimer's disease. secreted cystatin C activates TREM2-dependent microglial phagocytosis, reducing p...Li et al. described a tumor-derived neuroimmune mechanism that promotes clearance of established amyloid pathology in Alzheimer's disease. secreted cystatin C activates TREM2-dependent microglial phagocytosis, reducing plaques and improving cognition. This work introduces a context-dependent neuroimmune-modulatory strategy that shifts Alzheimer's therapy from broad immune activation toward substrate-coupled amyloid clearance.
CD8 T cell migration is central to host defense, enabling clonal selection, tissue infiltration, and elimination of infected cells. While chemokines guide these cells by activating Rac for F-actin polymerization, recent...CD8 T cell migration is central to host defense, enabling clonal selection, tissue infiltration, and elimination of infected cells. While chemokines guide these cells by activating Rac for F-actin polymerization, recent studies reveal a complementary mechanism through Rho activation. This pathway relies on tissue confinement, which deforms the nucleus, activates the actomyosin network, and allows CD8 T cells to use physical cues for surveillance without external signals. In this review article, we explore how chemokine- and mechanosensing-dependent pathways guide CD8 T cell surveillance and introduce a 'front-' versus 'rear-driven' motility model to illustrate their integration for effective tissue monitoring. Ultimately, the interplay of biochemical and physical cues ensures tissue-specific protection by T cells during homeostasis and inflammation.