Immunology最新文献

Tuberculosis (TB) remains a global health burden, particularly because of the limited efficacy of the Bacillus Calmette-Guérin (BCG) vaccine against adult pulmonary TB. To improve immunogenicity, we developed a recombinant BCG strain expressing the M. tuberculosis-specific antigen Rv1507A (rBCG_Rv1507A) and evaluated its immune-enhancing potential. rBCG_Rv1507A-infected human PBMCs and murine macrophages exhibited enhanced co-stimulatory marker expression and Th1-skewed cytokine profiles in vitro. The vaccine stimulated the expansion of T follicular helper (TFH) cells and both central and effector memory T cells. Intratracheal immunisation induced systemic and mucosal antibody responses, localized memory B cell formation, and enrichment of lung-resident memory T cells in vivo. Importantly, rBCG_Rv1507A promoted macrophage apoptosis and suppressed autophagy, which may support cross-antigen presentation. Furthermore, it induces features of trained immunity, including hematopoietic progenitor expansion and metabolic reprogramming of macrophages. These immunological enhancements were compartmentalized to the lungs, the primary site of TB infection, due to mucosal delivery. Collectively, rBCG_Rv1507A demonstrated potential as a next-generation TB vaccine by integrating durable adaptive memory with innate immune training. However, further studies are required to confirm its protective efficacy.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by chronic inflammation and immune dysregulation, with neutrophils playing a critical role in disease pathogenesis. In this study, we elucidated the involvement of the CXCL2-PI3K/AKT/NF-κB signalling axis in the abnormal activation of neutrophils in SLE using transcriptome analysis and functional experiments. Transcriptomic profiling revealed that CXCL2 expression is significantly upregulated in SLE patients, contributing to the activation of key inflammatory pathways and the expression of pro-inflammatory cytokines and chemokines. In vitro and in vivo experiments confirmed that CXCL2 promotes the transcription of inflammatory factors by activating the PI3K/AKT/NF-κB pathway, and inhibitors targeting this signalling axis effectively reduced inflammation. Furthermore, neutrophils from SLE patients exhibited a 'pre-activated' state under CXCL2 stimulation, potentially due to epigenetic or metabolic alterations. The functional relevance of CXCL2 was further validated in vivo, where knockout of CXCL2 or depletion of neutrophils reduced tissue damage and inflammatory responses. This study highlights the importance of the CXCL2-PI3K/AKT/NF-κB signalling axis in SLE and suggests that targeting CXCL2 or neutrophil-specific markers could provide novel therapeutic strategies for managing SLE. Future research should explore the heterogeneity of neutrophil subpopulations in SLE and the role of metabolic reprogramming in exacerbating inflammation, further refining potential targeted therapies.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease driven by neuroinflammation, where regulatory T cell (Treg) dysfunction exacerbates immune imbalance. This study explores whether Tui Na acupressure, a traditional Chinese therapy, can restore Treg immunosuppressive function through the FoxP3/mTORC1 signalling pathway to mitigate ALS pathology. In SOD1G93A ALS mice, Tui Na was applied at the Shenshu acupoint, with motor and cognitive functions assessed via rotarod, tail suspension, novel object recognition, and Y-maze tests. Multi-omics (transcriptomics, proteomics), flow cytometry, ELISA, and Western blot analysed Treg proportions, cytokine profiles, and pathway activation. In vitro assays evaluated Treg proliferation and immunosuppression. Tui Na significantly enhanced motor and cognitive performance, increased Treg proportions in spleen, lymph nodes, and blood, and elevated anti-inflammatory cytokines (IL-10, TGF-β) while reducing pro-inflammatory markers (IL-6, TNF-α). Transcriptomic and proteomic analyses revealed upregulated FoxP3, Mtor, and Raptor, with enhanced Treg proliferation and immunosuppression confirmed in vitro. Pathway inhibitors (GSK126, rapamycin) reversed these effects, confirming FoxP3/mTORC1 dependency. Tui Na also reduced apoptosis and oxidative stress, supporting immune regulation. These findings highlight Tui Na's potential to restore Treg-mediated immune balance in ALS, offering a non-pharmacological therapeutic strategy. This study provides novel immunological insights into Tui Na's mechanisms, advocating its clinical evaluation for ALS and related immune-driven disorders.

Human papillomavirus type 16 (HPV16) E6 and E7 are oncogenic proteins that are overexpressed following viral genome integration into the chromosomal DNA of infected mucosal epithelial cells, contributing to viral immune evasion and carcinogenesis. Epithelial cells can shed large extracellular vesicles (LEVs) that may modulate immune responses. We hypothesise that LEVs shed from epithelial cells expressing E6 and E7 modulate CD8⁺ T cell priming by the skin-local antigen presenting cells, the Langerhans cells (LCs). LEVs were isolated from control and E6/E7-expressing murine epithelial PDV cells. PDV-E6/E7 cells shed threefold more LEVs than control PDV cells in vitro. Murine LC 'like' cells were differentiated in vitro, co-cultured with LEVs, and assessed for antigen presentation, co-stimulatory molecule expression and cytokine production. We found that LCs co-cultured with Ctrl-LEVs demonstrated enhanced TAP1-dependent CD8 T cell priming, which was associated with increased co-stimulatory molecule and IL-12 expression. LCs co-cultured with E6/E7-LEVs failed to enhance TAP-1-dependent T cell priming and suppressed IL-12 production despite upregulating MHC-1 and co-stimulatory molecule expression. Our results show that LC priming of T cells is enhanced following treatment with Ctrl-LEVs whereas LEVs from HPV16 E6/E7 expressing cells suppress LC function. Functional impairment of LC priming of T cells by E6/E7-LEVs released in the epithelium may contribute to viral persistence in HPV16-infected skin.

Interleukin-4 (IL-4) drives Th2 polarisation and allergic inflammation, yet the epigenetic mechanisms regulating Il4 transcription in CD4⁺ T cells remain unclear. While STAT6 and GATA3 are canonical transcriptional regulators, lysine-specific demethylase 5A (KDM5A), an H3K4-specific demethylase, has not been linked to Th2 immunity. Here, we investigate KDM5A's role in IL-4 production and allergic airway disease (AA). Using DO11.10 TCR-transgenic mice and CD4⁺ T cell-specific Kdm5a-knockout models, we assessed KDM5A's role in IL-4 transcription. Chromatin immunoprecipitation (ChIP)-qPCR evaluated H3K4 demethylation at the Il4 promoter. Cross-ELISA quantified IL-4 secretion, and ubiquitination assays analysed KDM5A stability. Lactobacilli-derived DNA (LgDNA) was administered to disrupt the USP7-KDM5A axis in AA models. The results showed that KDM5A deficiency abolished TCR activation-induced IL-4 production, impairing Th2 polarisation. Mechanistically, KDM5A maintained H3K4 hypomethylation at the Il4 promoter, facilitating STAT6/GATA3 recruitment. TCR signalling enhanced KDM5A promoter occupancy via USP7-mediated deubiquitination. USP7 stabilisation of KDM5A elevated H3K4 demethylation and IL-4 transcription, driving AA pathogenesis. LgDNA suppressed USP7 activity, reducing KDM5A promoter binding by 65% and airway inflammation by 72%. In summary, KDM5A acts as an epigenetic rheostat of Th2 immunity, where USP7-dependent stabilisation licenses STAT6/GATA3 access to the Il4 promoter during TCR activation. Targeting the USP7-KDM5A axis with LgDNA selectively suppresses pathogenic Th2 responses while preserving physiological IL-4 functions. Our findings define a novel epigenetic mechanism for allergic disease and establish microbiome-derived LgDNA as a precision therapeutic strategy.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a polymorphic enzyme that shapes the peptide repertoire presented by MHC class I molecules and can regulate adaptive immune responses in cancer and autoimmunity. Common missense polymorphisms in ERAP1 modulate its activity and are found in specific allotypes in humans. ERAP1 allotypes are linked to predisposition to HLA-associated inflammatory diseases such as psoriasis and Behçet's disease, through the generation of specific CD8+ T cell populations targeting disease-specific HLAs. Given the established broad effects of ERAP1 activity on the cellular immunopeptidome, we hypothesised that ERAP1 allotypic variation may lead to broad immunopeptidome shifts capable of triggering the observed antigenic responses. To test this hypothesis, we generated two A375 melanoma cell lines, each one expressing one of the most common, disease-associated ERAP1 allotypes, namely allotypes 2 or 10. Comparison of the immunopeptidome of these two cell lines showed only minor differences in peptide sequences presented but extensive changes in abundance that included alterations in length distribution, binding affinity, and sequence motifs. Our results suggest that enzymatic differences between ERAP1 allotypes are reflected primarily in the quantitative composition of the cellular immunopeptidome. These quantitative changes may constitute a mechanism that underlies ERAP1-allotypic associations with HLA-associated autoimmunity and variable immune responses.

Inactivation of the BEACH (beige and chediak-higashi) family member NBEAL2 in humans and mice results in the development of the gray platelet syndrome (GPS), a bleeding disorder characterised by macrothrombocytopenia and splenomegaly. On the cellular level, NBEAL2 inactivation leads to functional defects in megakaryocytes, platelets, neutrophils and NK cells. In addition, Nbeal2 deletion in mice causes specific defects in mast cells (MCs), such as accumulation of transcription factors and proteins that are involved in the protein biosynthesis machinery. These defects culminate in non-physiological survival behaviour and an amplified stem cell factor (SCF)-, interleukin (IL)-3- and IL-33-induced cytokine production. Here we show that NBEAL2 deficiency also leads to an Abl1-supported increased surface expression of the multi-drug-resistant protein 1 (Mdr-1) ABCB1, which is antagonised by the IL-33-induced activation of the TAK1-IKK2 module and the activation of Src-family-kinases (SFKs). Our data demonstrate that NBEAL2 is required to control the surface expression of ABCB1.