Program stem-like CD8 T cells to enhance antiviral immunity against chronic viral infection

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PROJECT SUMMARY Chronic infection by viruses such as HIV, HBV, and HCV remains a major global health challenge. During chronic viral infection, CD8 T cells fail to eradicate the virus and develop into a dysfunctional state, termed exhaustion. Exhausted CD8 T cells, which were first characterized in mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, progressively lose effector function, upregulate inhibitory receptors, and exhibit dysregulated metabolism. Immunotherapies fail to completely reverse T-cell exhaustion or achieve sustained viral control during chronic viral infection. Thus, there is an unmet need to develop new strategies to overcome T-cell exhaustion and enhance the efficacy of immunotherapy against chronic viral infection. Although exhausted CD8 T cells were initially thought to be a homogeneous population, we and others have recently shown that a TCF1high antiviral CD8 T cell subset maintains long-term antiviral immunity through self-renewal and replenishing TCF1low terminally exhausted CD8 T cells during chronic viral infection. Importantly, these stem- like CD8 T cells are less exhausted and mediate the response induced by various immunotherapies. Our published studies have demonstrated stem-like CD8 T cells as a separate CD8 lineage with transcriptional and epigenetic programs that are distinct from those of terminally exhausted CD8 T cells and are tightly regulated by transcription factors, epigenetic regulators, and cytokines. The goal of this proposal is to define the molecular and cellular mechanisms regulating the immune response of stem-like CD8 T cells against chronic viral infection and evaluate strategies to improve antiviral immunity by targeting these pathways. Using chronic LCMV infection model, cutting-edge metabolic assay, multispectral quantitative imaging, and unique mouse genetic tools, we will identify the metabolic pathways and cell-cell interactions that endow stem-like CD8 T cells with their superior antiviral immunity and responsiveness to immunotherapies. These results will lay the foundation for the development of novel interventions to induce sustained control over chronic viral infections.