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

Publication Type:

Journal Article

Source:

Science (New York, N.Y.), Volume 335, Issue 6069, p.723-7 (2012)

Keywords:

2012, Adoptive Transfer, Animals, Autoantigens, CD8-Positive T-Lymphocytes, Cell Proliferation, Center-Authored Paper, Clinical Research Division, Consortium Authored Paper, Epigenesis, Genetic, February 2012, Gene Expression Profiling, Gene Expression Regulation, GENOMICS, homeostasis, Immunologic Memory, Lymphocyte Activation, Lymphocyte Count, Lymphopenia, MICE, Mice, Inbred C57BL, Mice, Transgenic, MICRORNAS, Oligonucleotide Array Sequence Analysis, Self Tolerance, Signal Transduction, T-Lymphocyte Subsets

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.