T cell exhaustion is common during chronic infections, cancer and prevents optimal immunity. Exhausted T cells are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity and poor survival following antigen stimulation. In addition, it has become clear that exhausted T cells co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating exhausted T cells. Our work has recently defined transcriptional networks of T cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes) in controlling the sustainability and terminal differentiation of exhausted T cell populations. We have found a key role for T-bet in sustaining a progenitor pool of exhausted CD8 T cells during chronic infection, while the related transcription factor Eomes governs terminal differentiation. Our new data indicates that PD-1, the major current target of immunotherapy approaches dramatically regulates these subsets of exhausted T cells and modulating PD-1 signals may have long-term impact on lineage dynamics of exhausted T cell populations. One key observation from these studies is that a key surrogate of reivingoration of exhausted CD8 T cell responses is a population of EomesHi PD-1Hi exhausted CD8 T cells. The use of this subset of CD8 T cells as a biomarker is explored. Ultimately, a more precise molecular understanding of T cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer.

Citation Format: E. John Wherry. Molecular basis of T cell exhaustion: Insights for immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA01.