Regulation of CD8+ T cell effector function during states of tolerance and exhaustion: Mechanisms and implications for immunotherapeutic approaches

CD8+ T cells have the capacity for potent anti-tumor and anti-viral immunity, but are often unable to wield this potential under conditions of prolonged antigen exposure because of the risk of immunopathology it poses to the host. Cancer and chronic viral infections are human diseases that develop as a result of suboptimal protection offered by functionally compromised CD8 + T cells. The ability to reduce virus or tumor load by targeting pathways regulating T cell responses has clearly demonstrated the potential benefit of reinvigorating a patient's CD8+ T cells. Still, a large number of patients fail to achieve sterilizing immunity or complete remission with current approaches. Thus, a better understanding of how CD8 + T cell effector activity is regulated could aid in the development of strategies offering better patient outcomes.;Mechanisms of peripheral self-tolerance that lead to the elimination or functional inactivation of tumor/self-reactive T cells have been identified as a primary barrier to CD8+ T cell immunotherapy of cancer. In Chapter 2, we review pathways contributing to T cell tolerance and immunotherapeutic approaches targeting these pathways. In Chapter 3, we identify a novel role for failed induction of the transcription factors, T-bet and Eomes, in T cell tolerance. Our studies further suggest active suppression of effector pathways invoked by these molecules when they are expressed in T cells within a tolerizing environment. We observe that inflammation can overcome these barriers and provide enhanced immunotherapy for tumor-bearing recipients. These findings elucidate molecular pathways that contribute to the phenotype of tolerant T cells and offer new, T cell-intrinsic targets for therapy.;Our lab previously reported that immunization through a second T cell receptor (not specific for persistent tumor/self-antigen) provided therapeutic benefit to leukemia-bearing recipients. Chapter 4 details our evaluation of an analogous approach in the context of chronic infection. We report that this strategy fails to improve responses of exhausted anti-viral CD8 + T cells, implying a distinct level of functional regulation in tolerant versus exhausted cells. Collectively, this work identifies novel regulatory mechanisms limiting CD8+ T cell effector function in distinct settings of prolonged antigen exposure that have the potential to inform new therapeutic approaches in patients.