Biology subjects

Dimeloe, S.

Publications and source records attributed to Dimeloe, S..

4 recordsLinked to original sources

bioRxiv2026

IL-17-producing CD8+ T cells differ in phenotype, metabolic profile and cytokine production to their CD4+ Th17 counterparts

Th17 cells (CD4+ T cells producing IL-17) are important for clearance of fungal infections and play a critical role in the development and exacerbation of numerous autoimmune diseases. Their differentiation, signalling pathways, cytokine production and metabolism are now well-characterised. As well as CD4+ T cells, CD8+ cells also produce IL-17 family members, and these have been named Tc17 cells. However, much less is known about their development, signalling or metabolism compared to their CD4+ counterparts. Here, we performed a series of in vitro and in vivo analyses of Tc17 cells as well as computational analysis of the published Tabula muris dataset, comparing Tc17 to IL-17- CD8+ T cells and to Th17 cells. We show that murine Tc17 cells are generated in the presence of TGF-{beta} and IL-6, and that cells produced by these culture conditions substantially reflect Tc17 cells seen in vivo; that is, with high expression of PD1, CD6, ICOS and CD161. Tc17 cells show phenotypic and functional differences to their Th17 counterparts, with increased production of IL-2 and IL-22 as well as an increased tendency to produce IL-17F as well as IL-17A. They show a more glycolytic profile than Th17 cells, with lowered mitochondrial membrane potential. This divergent phenotype and cytokine production suggests differential roles in vivo for these two cells.

immunology↗

bioRxiv2024

Vancomycin impairs macrophage fungal killing by disrupting mitochondrial morphology and function

Vancomycin is a widely prescribed antibiotic used in the treatment of Gram-positive bacterial infections. We recently showed that this antibiotic disrupted protective anti-fungal immune responses via microbiome dysbiosis, enhancing susceptibility to invasive candidiasis. Antibiotics are an independent risk factor for developing this life-threatening fungal infection, but whether microbiota-independent mechanisms also drive this association is not clear. Here, we show that vancomycin directly impairs macrophage responses to Candida albicans, the main causative agent of invasive candidiasis. Vancomycin-treated macrophages were less able to kill C. albicans despite normal phagocytosis rates and were hyper-inflammatory and more likely to die during infection. We found that vancomycin bound to macrophage mitochondria, leading to depolarisation, reduced respiratory capacity and a hyper-fragmented morphology associated with increased ROS production. Taken together, this work demonstrates direct effects of vancomycin on mammalian immune cells, helping us to understand pro-inflammatory effects of this drug and how it promotes susceptibility to life-threatening fungal infection.

immunology↗

bioRxiv2024

Proteomic analysis reveals dysregulation of peripheral blood neutrophils in patients with Multiple Sclerosis

Multiple Sclerosis (MS) is a complex auto-inflammatory disease affecting the brain and spinal cord, which results in axonal de-myelination and symptoms including fatigue, pain, and difficulties with vision and mobility. The involvement of the immune system in the pathology of MS is well established, particularly the adaptive T cell response, and there has been a particular focus on the IL-17-producing subset of Th17 cells and their role in driving disease. However, the importance of innate immune cells has not been so well characterised. Here we focused on neutrophils, which are innate immune cells and rapid responders to inflammation, and which have recently been linked to other chronic autoimmune conditions. Multiple strands of evidence in patients with MS and in mice with the experimental autoimmune encephalomyelitis MS model suggest neutrophils may play a role in driving MS inflammation. Here, we performed proteomic analysis on neutrophils from patients with MS and healthy donors, revealing striking differences. In particular, granule proteins were significantly more abundant in the MS neutrophils compared to the healthy controls, with a particular over-abundance of proteins in primary and secondary granules. In addition, members of the MAVS signalling pathway were differently regulated compared to healthy donor cells. Finally, we find that MS neutrophils do not suppress T cell activation equivalently to healthy neutrophils, and in particular are unable to suppress expression of CD161 on the T cells, indicative of Th17 differentiation. We propose that neutrophil dysregulation in MS may contribute to dysfunctional T cell responses.

immunology↗

bioRxiv2023

Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity

Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) reporter mice (Nr4a3-Tocky-Ifng-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic TILs exhibited a variety of activation defects, including IFN-{gamma} production decoupled from TCR signalling, decreased polyfunctionality and reduced TCM formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.

immunology↗