Characterization of islet-specific CD8 T cells in the honeymoon of type 1 diabetes

Informations projet

HONEYDIAB-8

N° de convention de subvention: 704974

DOI

10.3030/704974

Projet clôturé

Date de signature de la CE 9 Mars 2016

Date de début 15 Septembre 2016

Date de fin 14 Septembre 2019

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 183 454,80

Contribution de l’UE

€ 183 454,80

Coordonné par

KING'S COLLEGE LONDON
United Kingdom

Periodic Reporting for period 1 - HONEYDIAB-8 (Characterization of islet-specific CD8 T cells in the honeymoon of type 1 diabetes)

Période du rapport: 2016-09-15 au 2018-09-14

Résumé du contexte et des objectifs généraux du projet

Type 1 diabetes is an autoimmune disease that results from the immune attack against the β cells in the pancreas. It is one of the most common metabolic diseases in childhood, and its incidence is rising more than 3% per year. It has no cure yet, and because of its chronic nature, health problems often develop later in life. There is a need for understanding better the immune system’s failure in order to foster new therapeutic approaches. Therefore, strategies capable of arresting the ongoing autoimmune response and therefore maximizing β cell preservation are important research goals.

With that in mind, the main objective of this work was to characterise immunological changes linked to disease progression during the initial stages of type 1 diabetes, just after the diagnosis and for a period of up to two years.

The project developed satisfactorily. We identified an autoreactive T cell population in blood that correlates with the metabolic status of β cells in the pancreas of patients with type 1 diabetes.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We analysed blood samples from multiple patients with type 1 diabetes collected at six-month intervals over two years. We used optimised protocols to track changes in populations of autoreactive CD8 T cells in blood, and novel technologies to further characterise them.

Successfully, this work led us to a novel finding: we discovered that changes in autoreactive CD8 T cell populations positively correlated with changes in the β cell function, i.e. as β cell function decreases T cell levels decrease, and vice versa. The T cell population was defined by the expression of the marker CD57, or more specifically by CD57+ effector memory CD8+ T cell population. This finding means we identified a T cell population in the blood of patients with type 1 diabetes that is directly linked with ongoing β cell death in the pancreas.

To pursue this discovery and further characterise the T cell population of interest, we isolated CD57+, and CD57– T cells as a control population, from the blood of five individuals with type 1 diabetes and five healthy controls, and analysed the gene expression profile. We isolated the RNA from the samples and sequenced it. We observed that CD57+ cells showed a significant enrichment of expression of genes associated with cytotoxicity, compared with their CD57– counterparts, indicating a gene signature associated with enhanced effector function and immunogenicity. Data indicated that CD57+ cells are highly differentiated and antigen-experienced, capable of exerting immediate cytotoxic effects.

To better understand the differentiation pathway of the CD57+ cells, we studied the epigenetic landscape characterising the accessible regions of the chromatin in four individuals with type 1 diabetes and four healthy controls. In addition, we characterised the T cell receptor and RNA expression at single cell level in CD57+ T cells from two individuals with type 1 diabetes. We believe these results will help to identify key mechanisms involved in the differentiation and regulation of the CD57+ T cells, having a high impact in the understanding of the disease progression. Data are still under analysis.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The project is still in development. Results from the initial part were already published in 2018, in the Journal of Clinical Investigation, and data from the final part are in the last stages of analysis. We aim to understand how changes in T cells result in the final effector differentiation of CD57+ T cells through the study of the chromatin architecture, and finally, identify T cell receptors as well as gene expression at single cell level to fully define and characterise this CD57+ T cell population.

Importantly, results from this project can open opportunities with a high translational/clinical impact. Firstly, we described a link between a specific circulating autoreactive CD57+ T cell population in the blood and β cell loss in the pancreas, with potential use for immune monitoring. Secondly, we identified an autoreactive CD57+ T cell population directly linked to the β cell destruction, having potential for targeted immunotherapies.

We aim to publish the remaining results from the project in a scientific journal, and with all that, not only expand knowledge in the scientific community, but also foster new therapeutic approaches in type 1 diabetes field.

Project Summary. A – Aims and methodology. B – Results and potential future impact.