International immunology最新文献

The cluster of differentiation 155 (CD155) is highly expressed on tumor cells and augments or inhibits the cytotoxic activities of natural killer (NK) cells and T cells through its receptor ligands DNAX accessory molecule 1 (DNAM-1) and T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), respectively. Although CD155 is heavily glycosylated, the role of glycosylation of CD155 in the cytotoxic activity of effector lymphocytes remains unknown. Here, we show that the N-linked glycosylation at residue 105 (N105 glycosylation) in the first Ig-like domain of CD155 is involved in the binding of CD155 to both DNAM-1 and TIGIT. The N105 glycosylation also plays an essential role to induce signaling in both DNAM-1 and TIGIT reporter cells. Moreover, we show that the N105 glycosylation of CD155 contributes preferentially to the DNAM-1-mediated activating signal over the TIGIT-mediated inhibitory signal in NK cells. Our results demonstrated the important role of the N105 glycosylation of CD155 in DNAM-1 and TIGIT functions and shed new light on the understanding of tumor immune responses.

Lymphocyte homing to peripheral lymph nodes (PLN) is critical for immune surveillance. However, autoimmune diseases such as multiple sclerosis (MS) can occur due to excessive immune responses in the PLN. Here we show that 6-sulfo sialyl Lewis X (6-sulfo sLex) glycans on high endothelial venules that function as ligands for l-selectin on lymphocytes play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST)-1 and GlcNAc6ST-2 double-knockout mice lacking the expression of 6-sulfo sLeX glycans, the EAE symptoms and the numbers of effector Th1 and Th17 cells in the draining lymph nodes (dLN) and spinal cords (SC) were significantly reduced. To determine whether 6-sulfo sLeX could serve as a target for MS, we also examined the effects of anti-glycan monoclonal antibody (mAb) SF1 against 6-sulfo sLeX in EAE. Administration of mAb SF1 significantly reduced EAE symptoms and the numbers of antigen-specific effector T cells in the dLN and SC in association with suppression of critical genes including Il17a and Il17f that are involved in the pathogenesis of EAE. Taken together, these results suggest that 6-sulfo sLeX glycan would serve as a novel target for MS.

Previous observational and experimental studies have suggested a relationship between statin treatments and the augmentation of immunotherapy effects; however, the causal role of statin usage in promoting antitumor immunity remains largely unexplored. Utilizing large-scale genome-wide association studies, we conducted a Mendelian Randomization (MR) analysis to examine the association between genetically proxied inhibition of the gene for 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a specific target of statins, and 524 immunotherapy-related profiles, encompassing immune cells, inflammatory cytokines, immune checkpoints, and gut microbiota. Our findings indicated a suggestive association between statin therapy and proinflammatory as well as antitumor effects; notably, inhibition of HMGCR demonstrated a robust link with increased susceptibility of various immune cell types, including basophil cells, white blood cells, eosinophil cells, neutrophil cells, activated CD8+ T cells, dendritic cells, and natural killer cells; furthermore, a causal relationship was observed between statin use and a decrease in terminal CD8+ T cells, granulocytes, monocytes, and myeloid-derived suppressor cells; genetically proxied statin usage was also significantly associated with elevated levels of proinflammatory cytokines and immunotherapy-related gut microbiota; importantly, the potential inhibition of HMGCR in influencing the response to immunotherapy was confirmed in the real-world cohorts. This study provides novel insights into the regulatory role of HMGCR inhibition in antitumor immunity, suggesting that strategies targeting HMGCR or lipid regulation may hold therapeutic potential for enhancing the efficacy of immunotherapy.

Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves isolating T cells from a patient, culturing them ex vivo, then reinfusing the cells back into the patient. Although this strategy has shown remarkable efficacy in hematological malignancies, the solid-tumour microenvironment (TME) has presented serious challenges for therapy efficacy. Particularly, the TME has immunosuppressive signalling and presents a metabolically challenging environment that leads to T-cell suppression. T-cell metabolism is an expanding field of research with a focus on understanding its inherent link to T-cell function. Here, we review the current model of T-cell metabolism from naïve cells through effector and memory life stages, as well as updates to the model from recent literature. These models of metabolism have provided us with the tools and understanding to explore T-cell metabolic and mitochondrial insufficiency in the TME. We discuss manipulations that can be made to these mitochondrial and metabolic pathways to enhance the persistence of infused T cells, overcome the metabolically challenging TME and improve the efficacy of therapy in ACT models. Further understanding and investigation of the impact of metabolic pathways on T-cell performance could contribute to improving therapy efficacy for patients.

C-type lectin receptors (CLRs) are a family of pattern recognition receptors, which detect a broad spectrum of ligands via small carbohydrate-recognition domains (CRDs). CLEC12A is an inhibitory CLR that recognizes crystalline structures such as monosodium urate crystals. CLEC12A also recognizes mycolic acid, a major component of mycobacterial cell walls, and suppresses host immune responses. Although CLEC12A could be a therapeutic target for mycobacterial infection, structural information on CLEC12A was not available. We report here the crystal structures of human CLEC12A (hCLEC12A) in ligand-free form and in complex with 50C1, its inhibitory antibody. 50C1 recognizes human-specific residues on the top face of hCLEC12A CRD. A comprehensive alanine scan demonstrated that the ligand-binding sites of mycolic acid and monosodium urate crystals may overlap with each other, suggesting that CLEC12A utilizes a common interface to recognize different types of ligands. Our results provide atomic insights into the blocking and ligand-recognition mechanisms of CLEC12A and leads to the design of CLR-specific inhibitors.

The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting the epithelial barrier. Global pollution and environmental toxic agent exposure have worsened over six decades because of uncontrolled growth, modernization, and industrialization, affecting human health. Introducing new chemicals without any reasonable control of their health effects through these years has led to documented adverse effects, especially on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, have been shown to compromise the epithelial barrier integrity. This disruption is linked to the opening of the tight-junction barriers, inflammation, cell death, oxidative stress, and metabolic regulation. Consideration must be given to the interplay of toxic substances, underlying inflammatory diseases, and medications, especially in affected tissues. This review article discusses the detrimental effect of environmental barrier-damaging compounds on human health and involves cellular and molecular mechanisms.

Toxoplasma gondii is a pathogenic protozoan parasite of the Apicomplexa family that affects approximately 30% of the world's population. Symptoms are usually mild in immunocompetent hosts, but it can pose significant health risks to immunosuppressed patients and pregnant women. Current treatment options are limited, and new therapies and vaccines are needed. The innate immune system is the first to recognize T. gondii infection and activates pro-inflammatory cytokines and chemokines to promote acquired immunity. The IL-12/IFN-γ axis is particularly important, and when this pathway is inhibited, infection becomes uncontrolled and lethal. In mice, receptors such as Toll-like receptor 11 (TLR11), TLR12, and chemokine receptors are involved in T. gondii recognition and the modulation of immune responses. In humans, where TLR11 and TLR12 are absent, other mechanisms have been reported as the innate immune sensing system in T. gondii infection. Immune cells activated in response to infection produce interleukin (IL)-12, which stimulates the proliferation of natural killer cells and T cells and promotes the production of interferon (IFN)-γ. Several IFN-γ-induced anti-T. gondii defense mechanisms inhibit parasite growth. These include nitric oxide (NO) production, indoleamine 2,3-dioxygenase, and the destruction of parasitophorous vacuoles by IFN-γ-inducible immunity related GTPase groups (IRGs and GBPs). Recent studies focusing on the diversity of IRGs in rodents and effector molecules in T. gondii suggest that host immune mechanisms and pathogen immune evasion mechanisms have co-evolved. Furthermore, it has been suggested that cysts are not simply dormant during chronic infection. This review summarizes recent findings on anti-T. gondii innate, adaptive, and cell-autonomous immune responses.

The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on the gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including REG3γ, were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, the purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γ and fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3s) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.

Multiple sclerosis (MS) is an incurable chronic autoimmune disease affecting the central nervous system (CNS). Although IL-17-producing helper T (Th17) cells are thought to be one of the exacerbating factors in MS, the underlying pathogenic mechanism is incompletely understood. TNF receptor-associated factor 6 (TRAF6) deficient T cells exhibited enhanced Th17 cell differentiation, however, the physiological relevance of TRAF6 in T cells remains unknown. Here, we induced experimental autoimmune encephalomyelitis (EAE) in T cell-specific TRAF6 deficient (TRAF6ΔT) mice to investigate the role of TRAF6 in T cells during the course of MS using an EAE model. Although Th17 cell differentiation was enhanced in TRAF6ΔT mice, mutant mice were resistant to EAE. In contrast, TRAF6 loss did not affect regulatory T-cell differentiation. Consistent with the severity of EAE, a small number of infiltrating T cells and a small area of demyelination were observed in the CNS of TRAF6ΔT mice. Moreover, myelin oligodendrocyte glycoprotein-induced IL-17 production in TRAF6-deficient T cells was significantly suppressed. We further confirmed lower levels of CD69 and granulocyte-macrophage colony-stimulating factor in Th17 cells of TRAF6ΔT mice than in wild-type mice. In contrast, the expression of IL-10 and cytotoxic T-lymphocyte-associated protein 4 in T cells was significantly elevated in the absence of TRAF6 because of enhanced T-cell receptor signaling. Collectively, TRAF6 signaling in T cells contributes to the pathogenesis of EAE by regulating the pathogenicity and autoantigen reactivity of Th17 cells.

Ulcerative colitis (UC) is a chronic disorder of the large intestine with inflammation and ulceration. The incidence and prevalence of UC have been rapidly increasing worldwide, but its etiology remains unknown. In patients with UC, the accumulation of eosinophils in the large intestinal mucosa is associated with increased disease activity. However, the molecular mechanism underlying the promotion of intestinal eosinophilia in patients with UC remains poorly understood. Here, we show that uridine diphosphate (UDP)-glucose mediates the eosinophil-dependent promotion of colonic inflammation via the purinergic receptor P2Y14. The expression of P2RY14 mRNA was upregulated in the large intestinal mucosa of patients with UC. The P2Y14 receptor ligand UDP-glucose was increased in the large intestinal tissue of mice administered dextran sodium sulfate (DSS). In addition, P2ry14 deficiency and P2Y14 receptor blockade mitigated DSS-induced colitis. Among the large intestinal immune cells and epithelial cells, eosinophils highly expressed P2ry14 mRNA. P2ry14-/- mice transplanted with wild-type bone marrow eosinophils developed more severe DSS-induced colitis compared with P2ry14-/- mice that received P2ry14-deficient eosinophils. UDP-glucose prolonged the lifespan of eosinophils and promoted gene transcription in the cells through P2Y14 receptor-mediated activation of ERK1/2 signaling. Thus, the UDP-glucose/P2Y14 receptor axis aggravates large intestinal inflammation by accelerating the accumulation and activation of eosinophils.