Tired of relapsing: manipulating T cell exhaustion as a treatment for autoimmune disease. (360G-Wellcome-104064_Z_14_Z)

The clinical course of autoimmune and infectious disease varies greatly even between individuals with the same condition. Greater understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T cell exhaustion inhibits the immune response, facilitating viral persistence. I have shown that a common transcriptional signature reflecting high levels of CD8 T cell exhaustion predicts poor cl earance of chronic virus (HIV) but conversely predicts better prognosis during responses to persistent self-antigen in multiple autoimmune diseases. In autoimmunity, I found that where CD8 T cell exhaustion was high a concurrent signature of CD4 T cell costimulation was low and used this signature to identify specific costimulatory signals preventing the development of T cell exhaustion during in vitro culture. As the balance of costimulatory and coinhibitory signals dictates the emergence of T cell exhaustion during chronic viral infection, I plan to test whether T cell exhaustion can be induced during in vitro and in vivo models. My ultimate goal is to exhaust an autoimmune response as a novel, targeted treatment strategy. I aim for this work to form the basis of a future translational research programme.