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Science 335 (6069): 723-727

Copyright © 2012 by the American Association for the Advancement of Science

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

Andrea Schietinger,1,2 Jeffrey J. Delrow,3 Ryan S. Basom,3 Joseph N. Blattman,1,2,* Philip D. Greenberg1,2,{dagger}

Abstract: 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.

1 Department of Immunology, University of Washington (UW), Seattle, WA 98195, USA.
2 Program of Immunology, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA 98109, USA.
3 Genomics Shared Resource, FHCRC, Seattle, WA 98109, USA.

* Present address: School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.

{dagger} To whom correspondence should be addressed. E-mail: pgreen{at}u.washington.edu

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