Immune Network最新文献

Recent advances have highlighted the crucial role of metabolic reprogramming in shaping the functions of innate lymphoid cells (ILCs), which are vital for tissue immunity and homeostasis. As tissue-resident cells, ILCs dynamically respond to local environmental cues, with tissue-derived metabolites such as short-chain fatty acids and amino acids directly modulating their effector functions. The metabolic states of ILC subsets-ILC1, ILC2, and ILC3-are closely linked to their ability to produce cytokines, sustain survival, and drive proliferation. This review provides a comprehensive analysis of how key metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid oxidation, influence ILC activation and function. Furthermore, we explore the complex interactions between these metabolic pathways and tissue-specific metabolites, which can shape ILC-mediated immune responses in health and disease. Understanding these interactions reveals new insights into the pathogenesis of conditions such as asthma, inflammatory bowel disease, and cancer. A deeper understanding of these mechanisms may not only advance our knowledge of disease pathogenesis but also lead to the development of novel therapeutic strategies targeting metabolic pathways in ILCs to treat tissue-specific immune disorders.

Herein, we found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-unexposed individuals exhibited an increased frequency of CD4⁺ T cells against SARS-CoV-2 membrane (M) protein, suggesting that SARS-CoV-2 M-reactive cells may be primed by previous infection with common cold coronaviruses (CCCoVs). We confirmed that CCCoV M-reactive CD4⁺ T cells cross-recognize SARS-CoV-2 M in unexposed individuals. Among coronavirus disease 2019 (COVID-19) convalescents and unexposed individuals, SARS-CoV-2 M-reactive CD4⁺ T cells exhibited significantly lower functional avidity than CD4⁺ T cells reactive to other viruses. Importantly, convalescents from mild COVID-19 had SARS-CoV-2 M-reactive CD4⁺ T cells with significantly lower functional avidity than convalescents from severe COVID-19. The current data suggest that pre-existing CCCoV M-specific memory CD4⁺ T cells may contribute to controlling SARS-CoV-2 infection by cross-reactivity, leading to mild disease but leaving memory cells with low functional avidity to SARS-CoV-2 M due to incomplete homology. These data provide indirect evidence that pre-existing cross-reactive CD4⁺ T cells contribute to protection from severe COVID-19.

Rheumatoid arthritis (RA) is a systemic autoimmune disease closely associated with synovial tissue proliferation, pannus formation in small joints such as the hands, wrists, and feet, cartilage destruction, and systemic complications such as pulmonary, cardiovascular, neurological, and skeletal muscle lesions, glucocorticoid-induced osteoporosis and infections. The importance of confirming the diagnosis and determining local activity is given to the study of synovial fluid. A deep understanding of the pathological process in the joint in RA, characterized by changes in autoreactive CD4+ T cells, B cells, macrophages, inflammatory cytokines, chemokines, and autoantibodies, has now been achieved, although much remains to be explored. This article provides an updated overview of the pathogenesis of RA, revealing even more therapeutic targets for the intra-articular pathological process.

Adult stem cells are a rare population of undifferentiated cells present in almost all body tissues. Depending on their location, stem cells can differentiate into various tissue types, primarily contributing to maintenance, repair, and immune system regulation. Stem cell therapies have significant potential in regenerative medicine and treatment of inflammatory diseases. However, many factors must be considered for successful clinical commercialization, including enhancing therapeutic potential, ensuring product differentiation, and optimizing the manufacturing process for large-scale production. The development of sophisticated regulatory mechanisms may enhance therapeutic applications. The aryl hydrocarbon receptor (AhR) is expressed in all adult stem cells, and its activation and function are tightly regulated. Understanding the role and regulation of AhR is crucial for developing effective stem cell therapies. This review examines the role of the AhR in regulating the fundamental characteristics of adult stem cells, which may contribute to advancing adult stem cell therapies.

Sphingosylphosphorylcholine (SPC) is one of sphingomyelin-derived sphingolipids. SPC levels are increased in ascitic fluids of ovarian cancer patients and stratum corneum of atopic dermatitis (AD) patients. SPC has antitumor activity against several cancer cells by reducing proliferation and migration and increasing apoptosis in vitro. SPC can also cause scratching, potentially exacerbating symptoms of AD. However, the role of SPC in modulating immune responses, particularly in the differentiation of Th9 cells, which carry the most powerful antitumor activity among CD4⁺ T cells, has yet to be investigated. In this study, we found that SPC is another inducer of Th9 cell differentiation by replicating TGF-β. SPC upregulated Smad3, STAT5, and β-catenin signaling pathways. Increased Smad3 and STAT5 signaling pathways by SPC promoted the differentiation of Th9 cells and increased β-catenin signaling pathway resulted in a less-exhausted, memory-like phenotype of Th9 cells. Increased Smad3, STAT5 and β-catenin signaling pathways by SPC were mediated by increased mitochondrial ROS. These results suggest that SPC is an important endogenous inducer of Th9 cell differentiation and may be one of the targets for treating Th9-related diseases, and that enhancing Th9 differentiation by SPC may be helpful in adoptive T cell therapy for cancer treatment.

Pathogen-associated molecular patterns (PAMPs) are highly conserved motifs originating from microorganisms that act as ligands for pattern recognition receptors (PRRs), which are crucial for defense against pathogens. Thus, PAMP-mimicking vaccines may induce potent immune activation and provide broad-spectrum protection against microbes. Dextran encapsulation can regulate the surface characteristics of nanoparticles (NPs) and induces their surface modification. To determine whether dextran-encapsulated NPs can be used to develop antiviral vaccines by mimicking viral PAMPs, we synthesized NPs in a cyclohexane inverse miniemulsion (Basic-NPs) and further encapsulated them with dextran or tetramethylrhodamine isothiocyanate (TRITC)-dextran (Dex-NPs or TDex-NPs). We hypothesized that these dextran encapsulated NPs could activate innate immunity through cell surface or cytosolic PRRs. In vitro and in vivo experiments were performed using RAW 264.7 and C57BL/6 mice to test different concentrations and routes of administration. Only TDex-NPs rapidly increased retinoic acid-inducible gene I (RIG-I) at 8 h and directly bound to it, producing 120-300 pg/ml of IFN-α via the ERK/NF-κB signaling pathway in both in vitro and in vivo models. The effect of TDex-NPs in mice was observed exclusively with footpad injections. Our findings suggest that TRITC-dextran encapsulated NPs exhibit surface properties for RIG-I binding, offering potential development as a novel antiviral and anticancer RIG-I agonist.

Chimeric antigen receptor-transduced T (CAR-T) cell therapy is an effective cell therapy against advanced hematological tumors. However, the use of autologous T cells limits its timely and universal generation. Allogeneic CAR-T cell therapy may be a good alternative as a ready-to-use therapeutic. Graft-versus-host disease (GVHD) is an obstacle for allogeneic CAR-T cells, but can be prevented by TCR deletion through genome editing. However, the remaining TCR-positive cells must be eliminated by costly, large-scale magnetic cell separation. Therefore, an alternative method for removing TCR-positive cells is needed. In this study, we found that monovalent anti-CD3 Abs such as Fab and single-chain variable fragment (scFv), but not whole IgG, induce apoptosis of in vitro expanded T cells, thereby effectively depleting residual TCR-positive T cells during TCR-deleted CAR-T cell generation and ultimately preventing xenogeneic GVHD in vivo. Thus, monovalent anti-CD3 treatment during allogeneic CAR-T cell manufacturing would be an efficient method to prevent GVHD.

Immunological tolerance is a fundamental arm of any functioning immune system. Not only does tolerance mitigate collateral damage from host immune responses, but in doing so permits a robust response sufficient to clear infection as necessary. Yet, despite occupying such a cornerstone, research aiming to unravel the intricacies of tolerance induction is mired by interchangeable and often misused terminologies, with markers and mechanistic pathways that beg the question of redundancy. In this review we aim to define these boarders by providing new perspectives to long-standing theories of tolerance. Given the central role of T cells in enforcing immune cascades, in this review we choose to explore immunological tolerance through the perspective of T cell 'resistance to activation,' to delineate the contexts in which one tolerance mechanism has evolved over the other. By clarifying the important biological markers and cellular players underpinning T cell resistance to activation, we aim to encourage more purposeful and directed research into tolerance and, more-over, potential therapeutic strategies in autoimmune diseases and cancer. The tolerance field is in much need of reclassification and consideration, and in this review, we hope to open that conversation.

Systemic sclerosis (SSc) is a complex autoimmune disease with an unclear etiology and no effective treatments. Recent research has suggested involvement of the microbiome in SSc pathogenesis. This study aimed to identify specific microbial species associated with SSc and explore their therapeutic potential. Serum Abs against 384 intestinal microbial species revealed a significant depletion in Abs against Bifidobacterium longum in patients with SSc compared to healthy controls. In a bleomycin-induced SSc mouse model, oral administration of B. longum strain RAPO attenuated skin and lung fibrosis, accompanied by reduced infiltration of inflammatory monocytes/macrophages and downregulation of pro-inflammatory cytokines and chemoattractant Ccl2 genes in lymph nodes and fibrotic tissues. B. longum RAPO treatment restored fecal microbial diversity and augmented short-chain fatty acid (SCFA)-producing bacteria in the gut, leading to increased fecal butyrate levels and upregulated SCFA receptor Gpr41 in the mesenteric lymph node. In vitro, B. longum RAPO and its culture supernatant suppressed the expressions of pro-inflammatory cytokine genes in macrophages and inhibited myofibroblast differentiation in fibroblasts. These findings highlight the probiotic potential of B. longum RAPO in preventing tissue fibrosis by modulating macrophage activity and promoting the growth of SCFA-producing bacteria, underscoring the therapeutic potential of microbial modulation in SSc.

The human body contains a diverse array of microorganisms, which exert a significant impact on various physiological processes, including immunity, and can significantly influence susceptibility to various diseases such as cancer. Recent advancements in metagenomic sequencing have uncovered the role of intratumoral microbiome, which covertly altered the development of cancer, the growth of tumors, and the response to existing treatments through multiple mechanisms. These mechanisms involve mainly DNA damage induction, oncogenic signaling pathway activation, and the host's immune response modulation. To explore novel therapeutic options and effectively target and regulate the intratumoral microbiome, a comprehensive understanding of these processes is indispensable. Here, we will explore various potential actions of the intratumoral microbiome concerning the initiation and progression of tumors. We will examine its impact on responses to chemotherapy, radiotherapy, and immunotherapy. Additionally, we will discuss the current state of knowledge regarding the use of genetically modified bacteria as a promising treatment option for cancer.