CD4 T cell differentiation and regulation in autoimmune diabetes

Type 1 diabetes is an autoimmune disease in which cells of the immune system attack the pancreas and prevent it from producing insulin. Even if new insulin-producing cells are provided as a transplant, the immune system simply destroys these too. Medicines are available that suppress the entire immune system, but these have unwanted side effects. The key to successful treatment of type 1 diabetes is to pinpoint which cells cause disease so that these can be selectively targeted. We have performed a screen to characterise the immune cells that cause diabetes in a mouse model. This work has yielded a striking result; the cells are quite clearly a particular subset called follicular helper T cells. The possibility that this subset of immune cells could cause diabetes has not previously been explored. The proposed work seeks to investigate how these cells develop, and determine whether targeting this subset therapeutically can prevent or reverse diabetes. We will explore whether follicular helper T cells can be detected in blood samples from type 1 diabetes patients and will also take advantage of mouse diabetes models so we can test whether targeting these cells has beneficial effects.

The importance of CD4 T cells in driving autoimmune diabetes has been recognised for some time. According to the original Th1/Th2 paradigm of CD4 T cell differentiation, diabetes was initially attributed to the Th1 subset. However, numerous subsequent observations appear at odds with this conclusion. Recent work has highlighted the potential for additional lineage choices for CD4 T cells, including the capacity to become Th17 cells, follicular helper T (TFH) cells or even Treg. Microarray data obtained using our TCR transgenic model of diabetes suggest the novel possibility that the T cells responsible for this autoimmune disease are TFH cells, the subset that specialises in providing B cell help. The proposed experiments will elucidate the molecular control of TFH cell differentiation and test the hypothesis that these cells play a causal role diabetes. The work will also explore our recent finding that IL-21, the signature cytokine for TFH cells, can counteract Treg suppression, potentially rendering this subset un-suppressible. Collectively our studies will provide new insight into the cellular and molecular pathways that influence CD4 cell differentiation and homeostasis in the context of an autoimmune response. Extending this work directly into human disease, this project will enumerate cells bearing TFH markers in patients with type 1 diabetes (T1D) and ascertain the value of such proteins as biomarkers of disease onset and progression. These studies have the potential to identify new therapeutic targets for the treatment of autoimmune diabetes. Taken together, this proposal constitutes an integrated programme of work that takes advantage of transgenic and gene-deficient mouse strains to generate refined hypotheses for testing in T1D patients. Ongoing iteration between murine and human work will enrich both areas of research and will maximise our progress in understanding the immunological abnormalities underlying autoimmune diabetes.