Project ID CM-HD2025_11

ThemeCM-HD

Co Supervisor 1A Dr Esperanza Perucha Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyEmail

Co Supervisor 1B Prof Leonie Taams Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyEmail

2025 Project: Discovering new immunometabolic mechanisms that regulate the human immune response

Rationale: Alterations in the resolution of the immune response can lead to chronic inflammation, driving diseases such rheumatoid arthritis, atherosclerosis or obesity. Additionally, blocking the resolution phase can potentiate the immune response, desirable in settings such as cancer or infection. However, the molecular machinery that underpins this process is not well understood. Our laboratories have discovered signals that drive immunoresolution in human immune cells, specifically how the potent anti-inflammatory cytokine IL-10 is regulated by external signals, including a novel role of cellular metabolism in this process.

Aims: This project aims to uncover the molecular drivers of IL-10 expression and new candidate pathways that drive immunoresolution in human T cells. Once identified, pathways and molecules will be interrogated in different disease settings by analysing human samples from patients with chronic inflammatory diseases, metabolic disorders or cancer.

Techniques: This project will involve both dry and wet laboratory skills. Our laboratories have generated several -omics datasets (RNAseq, scRNAseq) that will be analysed by the student, together with publicly available ones, using R programming. Wet lab skills include general cellular and molecular immunoassays such as flow cytometry, proliferation, immune cell isolation and culture and quantitative PCR. For genetic manipulation we will employ cellular transduction techniques to generate polyclonal populations or target-specific (CAR-T cells, for example). Specific immunometabolic assays (Seahorse, cholesterol pathway assessments) and imaging techniques (i.e. Imagestream, confocal) will also be part of this project.

Objectives:
Year 1: molecular dissection of immunoresolution pathways in health. Interrogation of -omics datasets to discover new intersections between metabolism and immune signatures. In vitro validation of these pathways.
Year 2-3: follow up on the new signatures. Genetic manipulation in cell lines or primary cells.
Year 2-3: interrogate the relevant pathways in disease models by accessing our human samples biobank.

Representative Publications

Page R, Matinez O, Larcombe-Young D, Bugallo-Blanco E, Papa S, Perucha E. Metabolic armouring of CAR and TCR T cells. Research Square. https://www.researchsquare.com/article/rs-4020589/v1

Bibby JA, Purvis HA, Hayday T, Chandra A, Okkenhaug K, Rosenzweig S, Aksentijevich I, Wood M, Lachmann HJ, Kemper C, Cope AP, Perucha E. Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate. Nat Commun. 2020 Jul 8;11(1):3412. DOI: 10.1038/s41467-020-17179-4

Perucha E, Melchiotti R, Bibby JA, Wu W, Frederiksen KS, Roberts CA, Hall Z, LeFriec G, Robertson KA, Lavender P, Gerwien JG, Taams LS, Griffin JL, de Rinaldis E, van Baarsen LGM, Kemper C, Ghazal P and Cope AP. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nat Commun. 2019 Jan 30;10(1):498. DOI: 10.1038/s41467-019-08332-9

Psoriatic and rheumatoid arthritis joints differ in the composition of CD8+ tissue-resident memory T cell subsets. Povoleri GAM, Durham LE, Gray EH, Lalnunhlimi S, Kannambath S, Pitcher MJ, Dhami P, Leeuw T, Ryan SE, Steel KJA, Kirkham BW, Taams LS. Cell Reports. 2023 May 30;42(5):112514. doi: 10.1016/j.celrep.2023.112514. Epub 2023 May 16.

miR-155-overexpressing monocytes resemble HLAhighISG15+ synovial tissue macrophages from patients with rheumatoid arthritis and induce polyfunctional CD4+ T-cell activation. Olsson AM, Povoleri GAM, Somma D, Ridley ML, Rizou T, Lalnunhlimi S, Macdonald L, Rajasekhar M, Martinez-Nunez RT, Kurowska-Stolarska M, Taams LS. Clin Exp Immunol. 2022 Apr 4;207(2):188-198. doi: 10.1093/cei/uxab016.

IKZF3/Aiolos Is Associated with but Not Sufficient for the Expression of IL-10 by CD4+ T Cells. Ridley ML, Fleskens V, Roberts CA, Lalnunhlimi S, Alnesf A, O’Byrne AM, Steel KJA, Povoleri GAM, Sumner J, Lavender P, Taams LS. J Immunol. 2020 Jun 1;204(11):2940-2948. doi: 10.4049/jimmunol.1901283. Epub 2020 Apr 22.