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How do human islet-infiltrating CD8+ T cells cause type 1 diabetes?

How do human islet-infiltrating CD8+ T cells cause type 1 diabetes?

PhD/Honours project

Type 1 diabetes is an autoimmune disease caused by the CD4+ and CD8+ T-cell response 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.  The project has emerged from our recent work (Pathiraja et al. Diabetes 2015) where we isolated proinsulin specific CD4+ T-cell clones from within the pancreatic islets of an organ donor who suffered from type 1 diabetes. Building on our success in defining the specificity of islet-infiltrating CD4+ T cells (Pathiraja et al. Diabetes 2015), this project will analyse the antigen/epitope specificity of human islet infiltrating CD8+ T cells and characterize their frequency in the peripheral blood of people with and without type 1 diabetes. The aims of this project will be to:

  • Clone TCR genes from islet-infiltrating CD8+ T-cell clones;
  • Generate TCR transduced cell lines;
  • Screen TCR transduced cell lines for responses against primary human beta cell and Cos-7 cells transfected with plasmids encoding HLA class I molecules and beta-cell antigens.

In collaboration with Prof Ed Stanley at the MCRI, we have generated induced pluripotent stem cells (iPSC) and will use these cells 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. This work will fill a major gap in our knowledge of the pathogenesis of human type 1 diabetes.

Supervised by:

  • A/Prof Stuart Mannering
  • Disease Focus:

  • Type 1 diabetes
  • Research Unit:

  • Human T cell