Rescued Tolerant CD8 T Cells Are Preprogrammed to Reestablish the Tolerant State

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Science  19 Jan 2012:
DOI: 10.1126/science.1214277


Tolerant self-antigen specific CD8 T cells fail to proliferate in response to antigen, thereby preventing autoimmune disease. Using an in vivo mouse model, we show that tolerant T cells proliferate and become functional under lymphopenic conditions, even in a tolerogenic environment. However, T cell rescue is only transient, with tolerance reimposed upon lymphorepletion even in the absence of tolerogen, challenging the prevailing paradigm that continuous antigen exposure is critical to maintain tolerance. Genome-wide mRNA and microRNA profiling revealed that tolerant T cells have a tolerance-specific gene profile that can be temporarily overridden under lymphopenic conditions but is inevitably reimposed, which suggests epigenetic regulation. These insights into the regulatory mechanisms that maintain or break self-tolerance may lead to new strategies for the treatment of cancer and autoimmunity.