Type 1 diabetes (T1D) is an autoimmune disease that is caused by the T-cell mediated destruction of the pancreatic, insulin-producing, beta cells. Unusual for an autoimmune disease, T1D frequently develops in the first decades of life.Currently T1D is treated by frequent insulin injections which replaces the insulin normally produced by the beta cells. While insulin replacement has been a life-saving therapy for T1D it is not a cure and people with T1D have a shorter life expectancy than those without T1D.
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. Viral infections, particularly enterovirus infections, have been suggested to contribute to the onset of autoimmunity, but this remains controversial.
The goal of this project is to investigate if human islet-infiltrating CD4+ T cell recognise antigens derived from enteroviruses. We have amassed a large (100s)panel of CD4+ and CD8+ T-cell clones or T-cell receptors (TCRs) from 12deceased T1D donors. This is a powerful resource because it allows us to scrutinise the antigen specificity of human T cells that have infiltrated the pancreatic islets, the site of autoimmunity in T1D.
Finding enterovirus specific CD4+ T cells within the pancreatic islets of organ donors who had T1D would be important new evidence implicating entero viruses in the immune pathogenesis of T1D. On the other hand, if we find that islet infiltrating CD4+ T cells don’t recognise enterovirus antigens, this suggests that this virus does not play a direct role in the immune pathogenesis of human T1D.
This project will give the student an excellent training in immunology, particularly human T-cell immunology and autoimmunity. This project will make a significant contribution to understanding of the role of enteroviruses in human T1D.