Immunology最新文献

Genetic factors, including single-nucleotide variants (SNVs), may modulate disease course and therapeutic efficacy in patients with inflammatory bowel disease (IBD). We investigated the association between four SNVs in cytokine genes and clinical phenotype as well as the response to molecular-targeted drugs in patients with IBD. A total of 197 IBD patients (142 Crohn's disease [CD], 55 ulcerative colitis [UC]) undergoing targeted treatment were enrolled. The SNVs analysed were: TNFA rs1800629 (−308 G>A), TGFB rs1800471 (−codon 10 C>T), IL6 rs1800795 (−174 G>C), and IL10 rs1800896 (−1082 G>A). Biochemical response at 12 months (T12) was defined as C-reactive protein < 5.0 mg/L and faecal calprotectin < 250 μg/g at T12, in the absence of ongoing corticosteroid therapy. Among the SNVs analysed, the IL6 rs1800795 C allele was significantly associated with a younger age at diagnosis (p = 0.049), while the TNFA rs1800629 A allele was more frequently observed in patients with CD than in UC (p = 0.036). Regarding treatment response, 134 patients completed 12 months of molecular-targeted therapy and were included in the per-protocol analysis; 41.0% achieved biochemical remission at T12. The IL10 rs1800896 variant allele was significantly associated with remission (OR = 2.15, 95% CI: 1.03–4.44; p = 0.041). This association remained significant in multivariate analysis (aOR = 4.15, 95% CI: 1.49–11.56; p = 0.007), independently of clinical and treatment-related variables. In conclusion, genotyping of cytokine-related SNVs may help identify patients with a more aggressive disease phenotype and guide personalised treatment strategies in patients with IBD.

In people living with HIV (PLWH), persistent viral replication and antiretroviral therapy (ART)-associated toxicity contribute to T cell exhaustion, characterised by significant metabolic reprogramming that negatively impacts cellular function and longevity. Understanding the metabolic dysregulation in exhausted T cells could unveil novel therapeutic strategies to rejuvenate immune responses in PLWH. This study investigated the prevalence and metabolic gene expression profiles of exhausted CD8⁺ T cells across three PLWH cohorts: viremic treatment-naïve (TN), viremic treatment-failure (TF) and aviremic treatment-responders (TR). Our analysis revealed that the proportion of exhausted CD8⁺ T cells (PD1⁺CD107a⁻) was markedly higher in viremic TN (5.1%) and TF (4.2%) groups compared to the aviremic TR cohort (2.2%, p < 0.05). Similarly, the percentage of terminally differentiated T_EMRA cells (CCR7⁻CD45RA⁺) was elevated in TN (38.0%) and TF (44.7%) compared with TR (21.5%, p < 0.05), indicating a higher prevalence of late-stage differentiation and exhaustion in viremic individuals. NanoString analysis revealed a broad downregulation of metabolic genes in exhausted CD8⁺ T cells from viremic individuals, suggesting a shift toward a metabolically quiescent state akin to naïve T cells. Seahorse analysis revealed impaired mitochondrial respiration in CD8⁺ T cells from viremic PLWH, characterised by reductions in both ATP-linked respiration and proton leak. Furthermore, we reported that combined treatment with MitoTEMPO and N-acetyl-l-cysteine (NAC) improved mitochondrial function but failed to restore the effector capacity of CD8⁺ T cells. In summary, this study highlights the defective metabolic programming of exhausted CD8⁺ T cells in viremic PLWH, underscoring potential metabolic targets for therapeutic intervention.

A pivotal strategy in immuno-oncology is the initiation and modulation of adaptive immune responses. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), known for its role in protein homeostasis and functionality, is implicated in tumorigenesis. However, its part in the antitumor immunity mediated by CD8⁺ T cells in lung adenocarcinoma (LUAD) is not yet clear. We harnessed bioinformatics to evaluate the clinical relevance of UCHL1 in LUAD, performed IHC to detect the expression of UCHL1 in LUAD tissue, and utilised qPCR to assess UCHL1 levels in LUAD cells, exploring its correlation with the presence of CD8⁺ T cells. The effects of UCHL1 on CD8⁺ T cell vigour have been investigated using lactate dehydrogenase and enzyme-linked immunosorbent assay kits, as well as flow cytometry. The contribution of UCHL1 to ferroptosis was examined with ferrous ion and manganese dioxide assay kits, alongside western blot. Furthermore, we utilised bioinformatics software UbiBrowser and Hdock, in conjunction with co-immunoprecipitation (Co-IP), immunofluorescence, and IP methods, to dissect the interaction between UCHL1 and FHL2. Rescue experiments further clarified the mechanism by which UCHL1 modulates FHL2 in tumour immunity. In vivo experiments confirmed the promoting effect of UCHL1 on tumour growth. Elevated UCHL1 levels in LUAD tissues and cells were observed. Dampening UCHL1 triggered ferroptosis in LUAD cells, which in turn ramped up CD8⁺ T cell activity and enhanced their tumour-killing potential. Mechanistically, UCHL1 was shown to deubiquitinate the downstream factor FHL2, and knocking down FHL2 could counteract the immunosuppressive effects induced by high UCHL1 levels on CD8⁺ T cells. UCHL1 inhibitor LDN57444 significantly inhibited tumour growth in mice. Therapies aimed at the UCHL1/FHL2 axis could be effectively paired with immunotherapies, opening new avenues in cancer treatment strategies.

Mycobacterium tuberculosis (Mtb) effectively suppresses host immunity to ensure its survival. We have earlier shown that the Acr1 protein of Mtb can inhibit the differentiation of dendritic cells (DCs). Consequently, in the current study, we examined the role of Acr1 in mitigating autoimmunity. Initially, we observed that Acr1 skews the differentiation of DCs into functionally competent myeloid-derived suppressor cells (MDSC^Acr1) that chiefly secrete immunosuppressive molecules, expand regulatory T cells (Treg^Acr1) and attenuate inflammatory responses. Further, MDSC^Acr1 suppress Th17 cells. Acr1 expanded MDSCs with a concurrent increase in myelin oligodendrocyte glycoprotein (MOG)-specific Tregs and a decline in Th17 cells in a murine experimental autoimmune encephalomyelitis (EAE) model and prevented the onset of the disease. These results were further validated in the prophylactic model of EAE. Mechanistically, Acr1 activates Tregs and MDSCs via the TLR-4 pathway, implicating innate immune recognition in Mtb-induced suppression. The results indicate a potential role of Acr1 against autoimmune diseases.

Pyruvate dehydrogenase kinase 2 (PDK2) regulates glucose metabolism; however, its role in liver injury development is unknown. Therefore, this study aimed to explore the effects of PDK2 on liver injury using a concanavalin A (Con A)-induced acute liver injury mouse model. To understand the mechanisms by which PDK2 affects liver injury pathogenesis, network pharmacology analysis was performed to pinpoint the potential target genes and signaling pathways involved. Con A was used to induce acute liver injury in mice. Thereafter, PDK2 differential expression levels in the liver tissue of normal and liver injury mice were analyzed, and the effects of PDK2 inhibition on Con A-induced liver damage were assessed through biochemical analysis and observation of hepatic histopathological changes. Enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, flow cytometry, and western blotting were used to explore the possible mechanisms by which PDK2 affects liver injury. PDK2 was involved in liver injury progression, and pharmacological inhibition of PDK2 notably increased mouse survival, decreased serum alanine transaminase and aspartate aminotransferase levels, attenuated hepatic histopathological damage and apoptosis, and inhibited pro-inflammatory cytokine secretion and the activation of the mitogen-activated protein kinase/nuclear factor kappa B (MAPK/NF-κB) signaling pathway. Pharmacological inhibition of PDK2 markedly alleviated hepatic oxidative stress and elevated myeloid-derived suppressor cells (MDSCs) in the livers of acute liver injury mice. Overall, inhibiting PDK2 ameliorates Con A-induced acute liver injury by enhancing MDSCs accumulation and suppressing oxidative stress, the MAPK/NF-κB signaling pathway, and inflammation. These findings identify PDK2 as a promising therapeutic target for immune-mediated hepatitis.