Which epitopes do human islet-infiltrating CD8+ T cells ‘see’?

Research Opportunity
Project Status
Medicine and Radiology
St Vincent's Hospital
Supervisor Email Number Webpage
A/Prof Stuart Mannering Personal web page

Project Details

Type 1 diabetes is an autoimmune disease caused by the CD4+ and CD8+ T-cell responses against the insulin-secreting beta cells found in the islets of Langerhans in the pancreas. While CD4+ T cells are the principal regulators of the (auto)immune response, CD8+ T cells are believed to be the primary ‘killers’ of beta cells in type 1 diabetes.  However, the antigens/epitopes that are ‘seen’ by pathogenic CD8+ T cells are not defined. This is an important question because knowledge of the targets of CD8+ T cells is essential for the development of new therapies to prevent type 1 diabetes. In addition this is a major gap in our understanding of human autoimmunity in type 1 diabetes.

This question has not been addressed previously because human islet-infiltrating CD8+ T cells and HLA-matched beta cells have not been available. In our recent work (Pathiraja et al. Diabetes 2015) we isolated and characterised proinsulin specific CD4+ T-cell clones from within the pancreatic islets of an organ donor who suffered from type 1 diabetes. At the same time we isolated a large panel of CD8+ T cells. This gives us a unique panel of CD8+ T-cell clones strongly implicated in the pathogenesis of human T1D to study.

In collaboration with Prof Ed Stanley at the MCRI, we have generated induced pluripotent stem cells (iPSC) from the deceased organ donors from whom the islet infiltrating T cells were isolated. These iPSC will be used to generate beta cells that express the same HLA class I molecules at the T cells. In this way we will be able to test the islet-infiltrating CD8+ T cells for responses to autologous beta cells. This will form the basis of our efforts to identify the epitopes ‘seen’ by human islet-infiltrating CD8+ T cells.  These reagents give us, for the first time, the tools required to dissect human CD8+ T-cell responses to beta cells and reveal the immune responses underlying this incurable disease.

This project will give the student an in depth training in immunology, particularly in CD8+ T-cell immunology of type 1 diabetes. This is an ambitious project that will reward an enthusiastic student.

This project is conducted in St Vincent’s Institute of Medical Research, Human T-Cell Laboratory.

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Medicine and Radiology

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St Vincent's Hospital

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