T cell exhaustion is defined as a dysfunctional state of T cells and represents a prominent regulatory mechanism to curtail excessive immune response of activated T cells. Chronic antigen exposure is thought to be the most important driver of T cell exhaustion. Inducing T cell exhaustion in pathogenic T cells that destroy pancreatic beta-cells may be an important way of disarming T cells to prevent type 1 diabetes.
To study T cell exhaustion in the in the context of autoimmunity, we have generated transgenic NOD mice with chronic and inducible expression of a key islet antigens such as IGRP and insulin in the antigen presenting cells. Our recent data shows that chronic expression of islet antigens results in T cell exhaustion which may be useful in preventing diabetes.
We aim to analyse islet-antigen specific T cells in these models using flow-cytometry, biochemical inhibition of signalling pathways, cell-cytotoxicity assays and gene-expression analyses by RNA sequencing to determine the exact mechanisms by which T-cell exhaustion blocks diabetes development.