Abstract
Abstract Virus-specific CD8 T cells play a critical role in controlling chronic infections such as HIV and HCV, but progressively lose their antiviral functions during prolonged antigen exposure. Repression of CD8 T cell effector functions, commonly referred to as T cell exhaustion, limits the ability of the immune system to purge viral reservoirs from the host. Therapies that transiently rejuvenate exhausted virus-specific CD8 T cells have been highly successful at recovering antiviral functions, but a current challenge for the field is to identify mechanisms for stably reprogramming exhausted CD8 T cells so that recovered antiviral properties can be long-lived. We have recently demonstrated that epigenetic modifications acquired in pathogen-specific CD8 T cells during prolonged antigen exposure (chronic viral infections) reinforces T cell exhaustion. Using a mouse model system of chronic viral infection we investigated the role of Dnmt3a mediated de novo DNA methylation in regulating CD8 T cell exhaustion. Strikingly, conditional deletion of Dnmt3a in activated CD8 T cells blocked the cells from becoming exhausted. Moreover, in the absence of acquiring a de novo exhaustion program, pathogen-specific CD8 T cells are able to control what normally is a chronic viral infection. These results have significant implications for therapeutic strategies that utilize reactivation of host pathogen-specific CD8 T cells to control chronic viral infections or cancer.
Published Version
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