Project ID CM-HD2024_15


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

Additional Supervisor Prof. Timothy Vyse

Uncovering novel immunoregulatory mechanisms in human T cells

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. Hence, regulating the resolution of the immune response can be of benefit in many different disease settings. However, the molecular machinery that underpins this process is not well understood. Our laboratories have discovered signals that drive immunoresolution in human T cells, specifically how the potent anti-inflammatory cytokine IL-10 is regulated by external signals that control the expression of the transcription factor c-Maf. Moreover, we have also identified of a unique role of cellular metabolism in this process.

Aims: This project aims to uncover the molecular drivers of c-Maf expression, as well as the discovery of 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. Specific immunometabolic assays and imaging techniques (i.e. Imagestream) will also be part of this project.

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

– Cholesterol metabolism: a new molecular switch to control inflammation; Cardoso D, Perucha E; 2021. Clin Sci (Lond); DOI: 10.1042/CS20201394. – Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate; Bibby JA, Purvis HA, Hayday T, Chandra A, Okkenhaug K, Rosenzweig S, Aksentijevich I, Wood M, Lachmann HJ, Kemper C, Cope AP, Perucha E; 2020; Nature Communications; DOI: 10.1038/s41467-020-17179-4 – The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells; 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; 2019; Nature Communications; 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; 2023; Cell Reports. doi: 10.1016/j.celrep.2023.112514. – 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. 2022. Clin Exp Immunol. 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. 2020. J Immunol. doi: 10.4049/jimmunol.1901283.