Journal
SCIENCE
Volume 335, Issue 6069, Pages 723-727Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1214277
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Funding
- NIH [R01 CA033084, K01 CA117985, P30 CA015704-35]
- Korea Research Institute of Bioscience and Biotechnology [FND 7008-08]
- Pilot and Feasibility Project Award [P30 DK 56465]
- Cancer Research Institute
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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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