Defining the immune phenotype of extremely early-onset type 1 diabetes

Student thesis: Doctoral ThesisDoctor of Philosophy


Type 1 diabetes is a lifelong autoimmune disease that is very rarely diagnosed in the first two years of life. We recently described a novel T1D phenotype, termed extremely early-onset T1D (here referred to as EXE-T1D) characterised by the development of T1D very early in life, which is associated with rapid and complete b-cell destruction. I therefore hypothesise that EXE-T1D may be the consequence of a more aggressive form of autoimmunity than seen in individuals who develop T1D at a later age. In this thesis this hypothesis was tested by comparing the immune phenotype of individuals with EXE-T1D and individuals with childhood or adulthood-onset T1D. Specifically, the frequency and phenotype of islet-specific T cells was assessed using sensitive FluoroSpot assays, and unbiased immune phenotyping was undertaken using five broad flow cytometry panels. Assessment of b-cell-specific T cell responses showed lower autoreactivity in the blood of EXE-T1D, and a decreased proportion of IL-10 responses close to diagnosis, suggestive of reduced immune regulation. Phenotypic characterisation of the circulating immune system identified increased frequencies of activated circulating follicular helper (aTfh) and peripheral helper (aTph) T cells co-expressing PD-1 and ICOS in EXE-T1D. Detailed examination of the phenotypic characteristics of these cells by single-cell transcriptional profiling revealed minor phenotypic differences between clinical cohorts, including a reduction in cell populations expressing heat shock proteins (HSP) and genes associated with an interferon (IFN) response. This study has revealed novel immune phenotypes associated with EXE-T1D which are currently being investigated as biomarkers of rapid b-cell destruction in larger cohorts of individuals with T1D. This work may therefore guide the selection of patients suitable for specific immune-based therapies to halt disease progression.
Date of Award1 Jan 2024
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorTimothy Tree (Supervisor) & Deena Gibbons (Supervisor)

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