Thymocytes displaying self-reactive T cell receptors usually undergo negative selection in the thymus. Here we demonstrate that agonist peptides can promote positive selection of immature double-positive thymocytes into distinct lineages, varying with the agonist concentration and the animal's age. Microarray gene expression analyses showed broad transcriptional alterations in a set of transcripts associated with the innate immune system, as well as silencing of CD8β expression. The resulting CD8αα T cells showed a rapid effector cytokine response. Hence, T cells displaying self-reactive receptors can have the gene expression profile and phenotypic characteristics of innate immune cells.