β‐cell specific T‐lymphocyte response has a distinct inflammatory phenotype in children with Type 1 diabetes compared with adults

Arif, Sefina; Gibson, Vivienne B.; Nguyen, Vy; Bingley, Polly J.; Todd, John A.; Guy, Catherine; Dayan, Colin; Powrie, Jake; Lorenc, Anna; Peakman, Mark

doi:10.1111/dme.13153

Cited by 29 publications

(34 citation statements)

References 17 publications

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“…Furthermore, agerelated differences in islet infiltration have been described, with younger subjects showing a greater infiltration of immune cells, including CD8 + T cells as well as B lymphocytes (5). In addition, peripheral blood CD4 + T cell autoreactivity shows a greater target antigen breadth in children than in adults, and is especially focused on proinsulin, as appears to be the case for CD8 + T cell responses in the present study (37). Thus the accentuated relationships we observe between β cells and CD8 + T cells in young children point to distinct underlying immunological pathways, with associated implications for immune monitoring and therapeutic approaches in this patient subgroup.…”

Section: Figure 3 Gene and Protein Expression Profiles Indicate Enhasupporting

confidence: 64%

Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes

Yeo

Woodwyk

Sood

et al. 2018

Journal of Clinical Investigation

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In type 1 diabetes, cytotoxic CD8+ T cells with specificity for β cell autoantigens are found in the pancreatic islets, where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β cell-reactive CD8+ T cells that are detectable in the circulation, and their relationship to β cell function, are not known. Here, we tracked multiple, circulating β cell-reactive CD8+ T cell subsets and measured β cell function longitudinally for 2 years, starting immediately after diagnosis of type 1 diabetes. We found that change in β cell-specific effector memory CD8+ T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8+ T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer-specific protein of 37 kDa, and CD16, and reduced expression of CD28) compared with their CD57- counterparts, and network association modeling indicated that the dynamics of β cell-reactive CD57+ effector memory CD8+ T cell subsets were strongly linked. Thus, coordinated changes in circulating β cell-specific CD8+ T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.

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Section: Figure 3 Gene and Protein Expression Profiles Indicate Enhasupporting

confidence: 64%

Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes

Yeo

Woodwyk

Sood

et al. 2018

Journal of Clinical Investigation

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“…T cells generated after GAD-alum immunisation display a bifunctional Th1/Th2 phenotype The ELISpot and cytokine secretion analyses show that GAD-alum immunisation generates a GAD-specific Th2 response. We and others have previously reported that GAD-specific Th1 responses are a feature of the natural history of type 1 diabetes [12,19,20]. Since the proposed mechanism of action of GAD-alum is immune diversion of autoreactive Th1 to Th2 responses, we next examined the fate of anti-GAD Th1 responses present at baseline and their relationship to the development of treatmentinduced anti-GAD Th2 responses, using a FluoroSpot assay that simultaneously detects secretion of both IFN-γ and IL-13 on a single-cell-specific basis.…”

Section: Resultsmentioning

confidence: 95%

GAD-alum immunotherapy in type 1 diabetes expands bifunctional Th1/Th2 autoreactive CD4 T cells

et al. 2020

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Aims/hypothesis Antigen-specific therapy aims to modify inflammatory T cell responses in type 1 diabetes and restore immune tolerance. One strategy employs GAD65 conjugated to aluminium hydroxide (GAD-alum) to take advantage of the T helper (Th)2-biasing adjuvant properties of alum and thereby regulate pathological Th1 autoimmunity. We explored the cellular and molecular mechanism of GAD-alum action in the setting of a previously reported randomised placebo-controlled clinical trial conducted by Type 1 Diabetes TrialNet. Methods In the clinical trial conducted by Type 1 Diabetes TrialNet, participants were immunised with 20 μg GAD-alum (twice or three times) or alum alone and peripheral blood mononuclear cell samples were banked at baseline and post treatment. In the present study, GAD-specific T cell responses were measured in these samples and GAD-specific T cell lines and clones were generated, which were then further characterised. Results At day 91 post immunisation, we detected GAD-specific IL-13 + CD4 T cell responses significantly more frequently in participants immunised with GAD-alum (71% and 94% treated twice or three times, respectively) compared with those immunised with alum alone (38%; p = 0.003 and p = 0.0002, respectively) accompanied by high secreted levels of IL-13, IL-4 and IL-5, confirming a GAD-specific, GAD-alum-induced Th2 response. Of note, GAD-specific, IL-13 + CD4 T cells observed after immunisation co-secreted IFN-γ, displaying a bifunctional Th1/Th2 phenotype. Single-cell transcriptome analysis identified IL13 and IFNG expression in concert with the canonical Th2 and Th1 transcription factor genes GATA3 and TBX21, respectively. T cell receptor β-chain (TCRB) CDR3 regions of GAD-specific bifunctional T cells were identified in circulating naive and central memory CD4 T cell pools of non-immunised participants with newonset type 1 diabetes and healthy individuals, suggesting the potential for bifunctional responses to be generated de novo by GAD-alum immunisation or via expansion from an existing public repertoire. Conclusions/interpretation GAD-alum immunisation activates and propagates GAD-specific CD4 T cells with a distinctive bifunctional phenotype, the functional analysis of which might be important in understanding therapeutic responses.

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“…Samples were transferred in triplicate to pre-coated and blocked IFNγ ELISpot plates (U-Cytech) and incubated for 24 hours to capture cytokine released. Cytokine release was identified as per the manufacturer’s instructions and plates counted using the Bio-sys Bioreader, as described previously [ 23 – 29 ]. Results are expressed as stimulation indices (SI) normalised to diluent-only control per 3.3 x 10 5 cells (SIs of 2 and above were considered a positive response).…”

Section: Methodsmentioning

confidence: 99%

In silico and ex vivo approaches indicate immune pressure on capsid and non-capsid regions of coxsackie B viruses in the human system

et al. 2018

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Coxsackie B Virus (CBV) infection has been linked to the aetiology of type 1 diabetes (T1D) and vaccination has been proposed as prophylaxis for disease prevention. Serum neutralising antibodies and the presence of viral protein and RNA in tissues have been common tools to examine this potential disease relationship, whilst the role of anti-CBV cytotoxic T cell responses and their targets have not been studied. To address this knowledge gap, we augmented conventional HLA-binding predictive algorithm-based epitope discovery by cross-referencing epitopes with sites of positive natural selection within the CBV3 viral genome, identified using mixed effects models of evolution. Eight epitopes for the common MHC class I allele HLA-A*0201 occur at sites that appear to be positively selected. Furthermore, such epitopes span the viral genome, indicating that effective anti-viral responses may not be restricted to the capsid region. To assess the spectrum of IFNy responses in non-diabetic subjects and recently diagnosed type 1 diabetes (T1D) patients, we stimulated PBMC ex vivo with pools of synthetic peptides based on component-restricted sequences identified in silico. We found responders were more likely to recognize multiple rather than a single CBV peptide pool, indicating that the natural course of infection results in multiple targets for effector memory responses, rather than immunodominant epitopes or viral components. The finding that anti-CBV CD8 T cell immunity is broadly targeted has implications for vaccination strategies and studies on the pathogenesis of CBV-linked diseases.

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β‐cell specific T‐lymphocyte response has a distinct inflammatory phenotype in children with Type 1 diabetes compared with adults

Cited by 29 publications

References 17 publications

Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes

Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes

GAD-alum immunotherapy in type 1 diabetes expands bifunctional Th1/Th2 autoreactive CD4 T cells

In silico and ex vivo approaches indicate immune pressure on capsid and non-capsid regions of coxsackie B viruses in the human system

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