Immunology最新文献

Dress, R. J., Ho, W. W., Ho, V., et al., “A Novel Polymersome Nanocarrier Promotes Anti-Tumour Immunity by Improved Priming of CD8⁺ T Cells.” Immunology, 175 (2025): 21-35. https://doi.org/10.1111/imm.13903.

In the article, the affiliation of the author, Shrinivas Venkataraman, was incorrect.

The incorrect affiliation is:

Unilever Industries Private Limited, Singapore

The correct affiliation should be:

Unilever Industries Private Limited, Bangalore, India

The online version of the article has been corrected.

We apologize for this error.

Immunometabolism plays a pivotal role in T cell fate decisions, yet its specific contribution to human Th17 differentiation remains incompletely understood. Th17 cells, a subset of CD4⁺ T cells, are central to autoimmune pathogenesis through their secretion of pro-inflammatory cytokines. Elucidating the metabolic drivers of Th17 differentiation may reveal novel therapeutic targets. We investigated the role of mitochondrial activity in Th17 differentiation using an in vitro model with naïve human CD4⁺ T cells. Single-cell metabolic profiling and functional assays were used to characterise metabolic changes during differentiation. Th17 cells exhibited a hyperpolarised mitochondrial membrane potential (ΔΨ) compared to non-Th17 cells. Hyperpolarised ΔΨ cells displayed increased metabolic activity and enhanced differentiation capacity. Metabolic profiling at 48 h revealed an early reliance on glycolysis, followed by a shift toward increased dependence on oxidative phosphorylation (OXPHOS) by 96 h. Gene expression analysis indicated early upregulation of TEFM, a mitochondrial transcription regulator, at 48 h. By 96 h, ΔΨ hyperpolarised cells exhibited a downregulation of DRP1 and MFN2, genes responsible for mitochondrial fission and fusion. Functionally, ΔΨ hyperpolarised cells expressed elevated activation markers (CD69, CD25) but also showed increased exhaustion markers (TIGIT, PD-1), indicating a link between high metabolic activity and exhaustion. Additionally, these cells triggered weaker NF-κB and AP-1 signalling and secreted lower levels of effector molecules (IFN-γ, Granzyme B) than ΔΨ depolarised cells. In conclusion, mitochondrial activity critically shapes Th17 differentiation. Although hyperpolarised ΔΨ cells exhibit greater activation, they are more prone to exhaustion and reduced effector function. These findings offer insights into Th17 metabolic regulation and its therapeutic potential in autoimmune diseases.

Immunosenescence is the process of immune dysfunction and gradual deterioration of the immune system associated with aging, while cellular senescence is the stable cell cycle arrest that can occur in non-immune or immune cells in response to stress or damage. Immunosenescence significantly impacts both the innate and adaptive immune responses and is characterised by physical changes in lymphoid organs, as well as dysfunctions in cellular and molecular mechanisms. Key features of immunosenescence include T-cell dysfunction, thymic involution, B cell aging, an imbalance in the ratio of naïve to memory cells, chronic inflammation known as inflammaging and metabolic dysregulation. This decline in immune cell diversity and functionality contributes to various age-related diseases. Therefore, restoring a more ‘juvenile’ immune function in aging populations, through interventions targeting immunosenescence, holds promise for alleviating many age-related diseases and promoting healthier aging. In this review, we provide a comprehensive understanding of the interplay between the immune system and senescent cells in both healthy and disease contexts. We then dissect the immune dysfunction that occurs with aging, known as immunosenescence, and explore its impact on the health of elderly individuals. Finally, we discuss recent advances in targeting immune system aging to promote healthier longevity, with a special focus on Programmed Death-Ligand 1 (PD-L1), an emerging and promising target for therapeutic intervention.

With 1 in every 20 women afflicted, breast cancer is the most frequent malignant tumour in women and a significant health burden on women. Drug resistance in cancer is the key problem limiting current therapy approaches. Cyclooxygenase-2 (COX-2, namely PTGS2) is linked to immune evasion and chemoresistance in tumour cells, and it is frequently overexpressed in many forms of cancer. It is currently unclear how precisely this regulatory link functions in breast cancer, though. COX-2 expression in breast cancer was verified by this investigation. COX-2 knockdown was used to confirm COX-2 function in the malignant development of tumour cells and the stimulation of the JAK2/STAT3 signalling pathway. The survival of tumour cells was then assessed by co-culturing with CD8⁺ T cells or receiving chemotherapy after COX-2 was knocked down. To examine the function of the JAK2/STAT3 signalling system, cells from each group were then treated with a combination of COX-2 overexpression plasmid and JAK2/STAT3 inhibitor. The tissues and cells of breast cancer had elevated expression levels of COX-2. Following the downregulation of COX-2, breast cancer cells showed enhanced apoptosis, lower susceptibility to chemotherapy, impeded proliferation and epithelial-mesenchymal transition and were more readily destroyed by CD8⁺ T lymphocytes. Nevertheless, the opposite effects were shown when COX-2 was overexpressed, and JAK2/STAT3 inhibitors were able to reverse these effects. COX-2 activated the JAK2/STAT3 signalling pathway, which in turn promoted immune evasion and decreased chemosensitivity in breast cancer.

Extracellular vesicles (EVs) are ubiquitously secreted nanoparticles that modulate the activities of recipient cells either through the transfer of bioactive cargo or by surface receptor-mediated signalling. EVs derived from dendritic cells are increasingly recognised as promising platforms for therapeutic cancer vaccines, owing to their immunostimulatory cargo, their capacity to transfer preformed peptide-major histocompatibility complexes to antigen-presenting cells, and their ability, in some cases, to directly activate cognate T cells. Despite encouraging preclinical results, EV-based cancer vaccines have demonstrated limited clinical efficacy, constrained by suboptimal immunogenicity, poor lymphoid targeting, and suppression within the tumour microenvironment. Several strategies-including prioritising tumour-specific neoantigens, co-administering adjuvants and immunotherapies, optimising EV production and delivery protocols, and engineering EVs with tailored characteristics-aim to overcome these limitations and improve clinical outcomes.

Traditional DNA vaccines, typically administered via intramuscular injection with electroporation (IM-E), often cause discomfort and require trained personnel. Addressing these challenges, we developed multivalent DNA vaccines targeting both intracellular mature virion (IMV) and extracellular enveloped virion (EEV) proteins of the monkeypox virus (MPXV), designated as M2 (A29L, B6R), M3 (A29L, B6R, M1R) and M4 (A29L, B6R, M1R, A35R). These vaccine constructs were formulated into dissolvable microneedle array patches (D-MAPs) for intradermal delivery. Comparative studies in mice demonstrated that D-MAPs achieved approximately 70% delivery efficiency and elicited robust humoral immune responses in mice, including antigen-specific IgG and cross-neutralising antibodies against MPXV, VACV and ECTV-comparable to those induced by IM-E. Furthermore, D-MAP immunisation induced stronger T cell responses, particularly in the draining lymph nodes. Importantly, the multivalent DNA vaccines-especially M3 and M4-conferred substantial protection against lethal VACV-WR challenge, achieving levels of protection comparable to the traditional replication-competent smallpox vaccine TianTan (VTT), with significant viral suppression and mitigation of pathological damage. Collectively, this study provided valuable insights for the development of innovative MPXV DNA vaccines, highlighting a minimally invasive and suitable for field application with D-MAP with broad potential for combating mpox outbreaks and future orthopoxvirus pandemics.

Type 1 diabetes (T1D) in humans is associated with a higher Bacteroidetes:Firmicutes ratio and a higher abundance of Bacteroides genus members. Bacteroides fragilis (BF) is an integral component of the human colonic commensal microbiota. Here, we show that gut colonisation of specific pathogen-free (SPF) non-obese diabetic (NOD) mice by BF at a juvenile age induces a pro-inflammatory immune response and accelerated disease progression. NOD mice born to BF-monocolonised parents not only showed rapid disease progression compared to germ-free (GF) controls but also preserved accelerated disease onset and higher disease incidence upon conventionalisation, suggesting that BF contributes to a pro-inflammatory response and autoimmunity in T1D. Interestingly, we found that while gut microbiota composition was different in control and BF-colonised SPF mice, the presence of BF alone could significantly impact the acquisition of microbial communities upon conventionalisation of gnotobiotic mice. Bulk RNAseq analysis of colon tissues revealed profound differences in the gene expression pattern of GF and BF-monocolonised mice as well as their conventionalised counterparts, shedding light on the probable mechanisms contributing to accelerated disease onset in mice that are exposed to BF. We found that mucin production is downregulated and the abundance of mucin degraders such as Akkermansia muciniphila is profoundly lower in BF-colonised mice. Overall, these studies demonstrate that early life acquisition of BF-like distal gut commensals could have profound modulatory effects on the eventual overall gut physiology, microbiota structure, immune function, and β-cell specific autoimmune outcomes under genetic susceptibility.

Lung squamous cell carcinoma (LUSC) is a highly mortal cancer. Tertiary lymphoid structures (TLSs) play a crucial role in creating a specific and essential environment for the development of cellular and humoral immune responses against tumours. This study investigated the effect of TLSs on prognosis and the prediction of immunotherapy efficacy in LUSC. To investigate the association between TLSs and clinicopathological features, haematoxylin and eosin staining and multiple immunofluorescence staining were performed. A comparative examination of survival and the factors influencing it was carried out between the TLS−/+, high and low TLS density, immature tertiary lymphoid structures (imTLS) and mature tertiary lymphoid structures (mTLS) groups of patients. To further analyse the prognostic value of TLSs in the immunotherapy cohort of patients with LUSC, two hundred and ninety-seven patients with LUSC were enrolled in this study. Of these, 129 patients were harbouring TLS+. Cramer's V relationships analysis revealed that both Stage (p = 0.029) and PD-L1 ≥ 50% (p = 0.011) were significant predictors of TLS+. Cox proportional hazards model multivariate analysis showed that the TLS+ (p = 0.037), high TLS density (p = 0.014) and mTLS (p = 0.001) were associated with better overall survival (OS) in LUSC patients. Multivariate analyses confirmed that TLS+ was an independent prognostic predictor for OS in the LUSC immunotherapy cohort (p = 0.021). This study provided evidence that LUSC patients with TLS+, high TLS density and mTLS had a favourable prognosis, suggesting that TLSs are an independent positive prognostic factor for LUSC patients.