Regulation of CD8+ T cell responses to chronic virus infection

PROJECT SUMMARYVirus-specific CD8+ T cells are essential for immune defenses against many viruses. However, duringchronic infections in mice and humans, CD8+ T cells undergo excessive apoptosis or become functionallyinactive and unable to resolve infection. T cells fail to eliminate infection due to their sustained expression ofinhibitory receptors that actively suppress their antiviral activity. Despite evidence that therapeuticinterference with inhibitory receptor signaling can allow some T cells to recover function and reduce viralloads, there continues to be a need for improved methods to prevent T cell exhaustion from occuring or toreverse T cell exhaustion once it sets in. It is now understood that virus-specific T cell senescence and Tcell exhaustion are programmed epigenetically and guided by specific sets of transcription factors. Distinctepigenetic processes, including changes in the methylation status of histone-3 lysine-27 (H3K27) in CD8+ Tcells, contribute to the formation of memory T cells, as well as functionally inactive subsets during chronicinfection. The role of specific enzymes in this process is poorly understood. We recently identified a criticallink between CD8+ T cell expression of UTX, an H3K27 demethylase, and impaired CD8+ T cell responsesto chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Virus-specific CD8+ T cells lackingUTX showed improved accumulation and maintenace over time, reduced expression of the inhibitoryreceptors, and were resistant to apoptosis. Our data suggest that UTX restricts virus-specific CD8+ T cellresponses by increasing T cell expression of inhibitory receptors, perhaps converting cells with memorypotential into functionally exhausted or senescent cells. Our central hypothesis is that UTX controls T celldifferentiation through a mixture of demethylase-dependent and demethylase-independent mechanisms thatpromote gene expression, including at inhibitory receptor loci. In Aim1 we determine the temporalrelationship between UTX and CD8+ T cell differentiation into functional or dysfunctional T cell subsets. InAim2, we investigate the role of UTX-mediated demethylase activity in regulating gene expression and Tcell effector functions and maintenance during infection. In Aim3, we explore the role of UTX interactingpartners, including T cell-relevant transcription factors and an H3K4 methyltransferase, in guiding T celldifferentiation and antiviral functions. Information from this project will be useful for comprehending howepigenetic changes due to histone methylation guide CD8+ T cell exhaustion. Long-term, our research mayimplicate the use of pharmacologic inhibitors of UTX to improve CD8+ T cell-mediated immune defenses.