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Science. 2012 Feb 10;335(6069):723-7. doi: 10.1126/science.1214277. Epub 2012 Jan 19.

Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state.

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Department of Immunology, University of Washington (UW), Seattle, WA 98195, USA.


Tolerant self-antigen-specific CD8 T cells fail to proliferate in response to antigen, thereby preventing autoimmune disease. By 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 (self-antigen), challenging the prevailing paradigm that continuous antigen exposure is critical to maintain tolerance. Genome-wide messenger RNA 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.

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