The impact of inflammatory context on the metabolic profile of T follicular helper cells

Jones, Jack (2025) The impact of inflammatory context on the metabolic profile of T follicular helper cells. PhD thesis, University of Glasgow.

Abstract

T follicular helper (Tfh) cells are a subset of CD4⁺ T cells that are key in driving the Germinal Centre response, assisting B cells to produce high-affinity antibodies during the adaptive response. Tfh cell differentiation/function is metabolically regulated; however, characterisation of Tfh cell metabolism during a type 2 helminth infection (e.g. H. polygyrus ), and its relationship to Tfh cells derived from type 1 inflammation, remains poorly understood. To date, Tfh cell metabolism in comparison to other T effector cells (Th1/Th2) remains understudied. This thesis aims to define the key metabolic pathways utilised by murine Tfh cells compared to other CD4⁺ T cell subsets, in Th1 (IAV Infection) and Th2-mediated inflammation (H. polygyrus ). Both infections induce strong Tfh and T effector cell responses. Using metabolic profiling techniques (METFLOW, PHOSFLOW, lipid assays, bulk RNA sequencing), I demonstrated that Tfh cells are metabolically active, capable of lipid accumulation and show lipid-dependent gene expression profiles, albeit less so than Th2 cells in H. polygyrus infection. Thus, Tfh cells favoured increased glycolytic gene expression over Th2 cells; however, Th2 cells have increased expression of genes associated with lipid and cholesterol pathways. To assess variation in Tfh metabolism across inflammatory contexts, I used bulk RNAseq to compare metabolic gene expression in Tfh cells from both Th1- and Th2-driven infections. My analysis revealed that Tfh2 cells (type 2) consistently display increased gene expression for lipid metabolism compared to Tfh1 (type 1), regardless of anatomical location or infection. Further to this, I found that in human in vitro-derived Tfh cells, acute inhibition of SCD-1, a key enzyme in lipid biosynthesis, facilitated a reduction in CXCR5 (and possibly CCR7) expression on the surface of Tfh cells. This indicates that manipulation of lipid metabolism directly influences Tfh cell biology and could possibly prevent their migratory capacity. Overall, my data shows that Tfh cell metabolism does not exhibit a fixed phenotype and that it can alter depending on the immune environment. Furthermore, this increases understanding of key metabolic nodes of Tfh cells, like lipid biosynthesis and the role of SCD-1, suggesting that metabolic manipulation may be a viable strategy for the selective modulation of Tfh cells. This is crucial as, to date, no therapies specifically target Tfh cells; however, with further research, we may be able to target Tfh immunometabolism effectively to enhance vaccine efficacy or, in cases of aberrant Tfh cell responses, modulate these responses in favour of the patient's needs.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Perona-Wright, Professor Georgia and Harnett, Professor Margaret
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85596
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2025 09:52
• Last Modified: 19 Nov 2025 12:01
• Thesis DOI: 10.5525/gla.thesis.85596
• URI: https://theses.gla.ac.uk/id/eprint/85596

Related URLs

• Article DOI