Type 1 diabetes (T1D) is an autoimmune disease caused by the combined action of CD4+ and CD8+ T-cell response against the insulin-secreting beta cells which are found within the islets of Langerhans in the pancreas. The adaptive immune response has many ‘check and balances’ that prevent, or attenuate harmful immune responses. CD4+ regulatory T cells, known as Treg, play an important role in maintaining immune tolerance and curbing undesirable immune responses. Tregs work similarly to CD4+ T helper, or effector, cells. They use their T-cell receptor (TCR) for antigen to ‘recognise’ peptide antigens presented by HLA-Class II. However, unlike Teff, which after TCR mediated activation secrete cytokines that ‘activate’ other immune cells in the vicinity, Treg actively suppress the effector function of neighbouring immune cells.
Regulatory T -cell responses are thought to play a central role in the development of autoimmune diseases, like T1D. For an autoimmune disease to manifest, the ‘self’ reactive immune cells must avoid, or be refractory to, the function of regulatory T cells. Boosting the number and/or the activity of autoantigen specific Treg is a promising therapeutic avenue for developing new therapies for autoimmune diseases, including T1D.
Harnessing Treg to prevent, or reverse, autoimmune diseases is hampered by difficulties in measuring the number and function of self-antigen specific CD4+ Treg. Treg function can be measured in vitro using purified cell populations, stimulated with an anti-CD3 mAb. Anti-CD3 stimulates all T cell irrespective oft heir antigen specificity. However, it has proven to be much more difficult to measure antigen specific Treg function. In our work to address this problem we have recently acquired data that suggests that we may be able to measure the function of human beta cell antigen specific Treg.
Hence, the aim of this project is two-fold. First to validate that the responses we are seeing are CD4+ regulatory T-cell responses. The second aim is to dissect the mechanism by which this Treg functions mediated.
This project will give the student an excellent training in immunology, particularly human T-cell immunology and autoimmunity. In the longer term this work will contribute to understanding of human Treg function, which has very important implications for both the diagnosis and developing new antigen specific therapies to prevent T1D.