The immune pathogenesis of T1D is poorly understood. It is clear that both CD4+and CD8+ T cells work together to mediate beta-cell destruction. However, it remains unknown ‘how and why’ the immune system targets the insulin-producing cells in people who develop T1D.
Recently we helped to identify an entirely new class of antigen, known as HybridInsulin Peptides (HIPs). HIPs are neoepitopes formed by the fusion of two beta-cell granule proteins and are recognised by pathogenic CD4+ T-cells in the NOD mouse and by human islet-infiltrating CD4+ CD4+ T cells. Currently less than 20HIPs recognised by human CD4+ T cells have been reported. Because a HIP can be formed by fusing any two protein fragments, it has been very challenging to identify new HIPs.
To overcome this technical challenge, we have established an antigen screening platform that has allowed us to identify new HIPs from a library of over 4,000candidate HIPs. The strength of our approach is that we use CD4+ T cells isolated from the pancreatic islets of deceased organ donors who had T1D.
This ensures that we identify antigens that are clinically relevant to the development of T1D. In our first project we used HIPs formed by the fusion of fragments of proinsulin to other proinsulin fragments (manuscript in preparation).Now we’d like to explore HIPs formed by the fusion of proinsulin with other beta-cell proteins.
The gaol of this project is to apply our HIPs screening platform to identifying HIPs formed by the fusion of proinsulin with other beta cell granule proteins. This project will leverage our established optimised work-flow and our large (100s)panel of CD4+ T-cell clones from 12 deceased T1D donors.
This project will give the student an excellent training in T-cell immunology, particularly human T-cell immunology and autoimmunity. This project will build on our current work to further explore the array of HIPs recognised by human T cells in T1D.