Normal mice are shown to harbor T cells that can be sensitized to proliferate against autologous red blood cells (RBC). These autoreactive cells were primed in vitro and in vivo with mouse as well as heterologous rat RBC, the in vivo administration of which has been previously shown to trigger the production of auto-RBC antibodies. Two broad classes of specificity are detected following priming: T cells cross-reactive for similar determinants coexpressed by mouse and rat RBC, and T cells specific for antigens restricted to self-RBC. These findings indicate that clonal deletion of self-RBC-reactive T cells is far from complete. The comparison of different in vitro and in vivo immunization protocols revealed the possible existence of several levels of immunoregulatory control which may prevent the expression of autoimmunity by these T cells.