A major goal is to understand the mechanisms of T cell exhaustion during chronic infections. During chronic viral infections, virus-specific CD8 T cells often lose effector functions and fail to acquire key memory T cell properties (i.e. become exhausted). Using approaches including multiparameter flow cytometry, systems biology and global gene expression profiling and genetically modified mice we are defining cellular and transcriptional pathways involved in T cell exhaustion and normal memory T cell differentiation. Pathways such as the inhibitory receptor PD-1 identified by these approaches are now major targets for cancer immunotherapy.
Some of areas of considerable current interest include inhibitory receptors (e.g. PD-1, LAG-3), transcription factors and inflammatory pathways. In addition, we are examining how co-infection with two pathogens can impact T cell memory.
In addition, we are investigating the mechanisms of T follicular helper cell responses in humans following influenza vaccination, enteric viral infection and age-related changes in T cell immunity in both mice and humans.