European Journal of Immunology最新文献

Macrophage activation syndrome (MAS) exemplifies a severe cytokine storm disorder with liver inflammation. In the liver, classical natural killer (cNK) cells and liver-resident type 1 innate lymphoid cells (ILC1s) dominate the ILC population. Thus far, research has primarily focused on the corresponding role of cNK cells. Considering the liver inflammation and cytokine storm in MAS, liver-resident ILC1s represent an interesting population to explore due to their rapid cytokine production upon environmental triggers. By utilizing a Toll-like receptor (TLR)9- and TLR3:4-triggered MAS model, we showed that ILC1s highly produce IFN-γ and TNF-α. However, activated ILC1s undergo apoptosis and are strongly reduced in numbers, while cNK cells resist inflammation-induced apoptosis. Signs of mitochondrial stress suggest that this ILC1 apoptosis may be driven by inflammation-induced mitochondrial impairment. To study whether early induction of highly cytokine-producing ILC1s influences MAS development, we used Hobit KO mice due to their paucity of liver ILC1s but unaffected cNK cell numbers. Nevertheless, neither the severity of MAS features nor the total inflammatory cytokine levels were affected in these Hobit KO mice, indicating that ILC1s are dispensable for MAS pathogenesis. Collectively, our data demonstrate that ILC1s undergo apoptosis during TLR-triggering and are dispensable for MAS pathogenesis.

B-1 cells are crucially involved in immune defense and regulation of inflammation and autoimmunity. B-1 cells are predominantly located in the peritoneal and pleural cavities, although body cavity B-1 cells recirculate systemically under steady-state conditions. The chemokines CXCL12 and CXCL13 have been identified as the main regulators of peritoneal B-cell trafficking. In mice deficient for sphingosine-1-phosphate receptor 4 (S1PR₄), B-1a and B-1b cell numbers are reduced in the peritoneal cavity by an unknown mechanism. In this study, we show that S1PR₄-mediated S1P signaling modifies the chemotactic response of peritoneal B cells to CXCL13 and CXCL12 in vitro. In vivo, S1PR₄-mediated S1P signaling affects both immigration into and emigration from the peritoneal cavity. Long-term reconstitution experiments of scid mice with wt or s1pr₄ ^-/- peritoneal B cells revealed a distinct distributional pattern in secondary lymphoid organs. As a functional consequence, both plasmatic and mucosal IgM levels, the main product of B-1a cells, are reduced in mice reconstituted with s1pr₄ ^-/- peritoneal cells. In summary, our data identify S1PR₄ as the second S1P receptor (besides S1PR₁), which is critically involved in the regulation of peritoneal B-1 cell function.

Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the "macrophage niche". This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in health and disease. Macrophage metabolism is central to their ability to switch between proinflammatory and anti-inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behavior. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to managing diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement.

Follicular helper (Tfh), peripheral helper (Tph), and regulatory (Treg) T cells are involved in myasthenia gravis (MG) pathogenesis, an autoimmune disorder arising from autoantibodies targeting neuromuscular junction proteins. This study explores the impact of low-dose IL-2 on Tfh, Tph, and Treg cells in vitro in MG. Acetylcholine-receptor antibody-positive MG (AChR-MG), muscle-specific kinase antibody-positive MG (MuSK-MG) patients, and healthy controls (HC) were studied. Blood cells were cultured with/without IL-2 and compared by the ratios of IL-2 stimulated/unstimulated cultures. In both AChR-MG and MuSK-MG patients, CD25⁺FoxP3⁺Tregs were lower, while CXCR5⁺PD-1⁺ or ICOS⁺Tfh and CXCR5⁻PD-1⁺ or ICOS⁺Tph cells were higher compared with HC. Among the MG group, the FoxP3⁺ Treg cells in AChR-MG patients were even lower compared with MuSK-MG patients. In vitro IL-2 stimulation increased Tregs in all groups while decreasing PD-1⁺/ICOS⁺Tfh and PD-1⁺/ICOS⁺Tph populations. The fold-increase ratio of Tregs and the fold-decrease ratio of PD-1⁺ or ICOS⁺Tfh and ICOS⁺Tph cells in AChR-MG and MuSK-MG patients were greater than in HCs. Low-dose IL-2 treatment may balance Tfh, Tph, and Treg cells in MG patients, offering a potential opportunity for disease modulation.

Lipid nanoparticles (LNPs) have emerged as the preeminent nonviral drug delivery vehicles for nucleic acid therapeutics, as exemplified by their usage in the mRNA COVID-19 vaccines. As a safe and highly modular delivery platform, LNPs are attractive for a wide range of applications. In addition to vaccines, LNPs are being utilized as platforms for other immunoengineering efforts, especially as cancer immunotherapies by modulating immune cells and their functionality via nucleic acid delivery. In this review, we focus on the methods and applications of LNP-based immunotherapy in five cell types: T cells, NK cells, macrophages, stem cells, and dendritic cells. Each of these cell types has wide-reaching applications in immunotherapy but comes with unique challenges and delivery barriers. By combining knowledge of immunology and nanotechnology, LNPs can be developed for improved immune cell targeting and transfection, ultimately working toward novel clinical therapeutics.