In the immune system, loss of tolerance to self can have devastating consequences, such as the development of autoimmune diseases. In some cases, however, we may wish to be able to break tolerance—for example, to activate immune cells to fight tumors. Schietinger et al. (see the Perspective by Lee and Jameson) used a combination of genetic mouse models and adoptive immune cell transfers to better understand the mechanisms regulating tolerance in T lymphocytes. In contrast to the prevailing paradigm, the maintenance of T lymphocyte tolerance did not require the continuous presence of antigen. Tolerance was able to be broken when previously tolerized cells were placed in an environment depleted of immune cells. However, when lymphocyte numbers were restored, cells were once again tolerized, even in the absence of antigen. These data, together with gene expression profiling, suggest that tolerance is associated with a specific gene expression program that, although possible to override temporarily, is reimposed by epigenetic mechanisms.
A. Schietinger, J. J. Delrow, R. S. Basom, J. N. Blattman, P. D. Greenberg, Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state. Science 335, 723–727 (2012). [Abstract] [Full Text]