Foxp3 instability leads to the generation of pathogenic memory T cells in vivo

Regulatory T (T(reg)) cells play a central role in maintaining immune homeostasis. However, little is known about the stability of T(reg) cells in vivo. In this study, we demonstrate that a significant percentage of cells exhibited transient or unstable Foxp3 expression. These exFoxp3(+) T cells express an activated-memory T cell phenotype, and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers increased in inflamed tissues under autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid-onset of diabetes. Finally, T cell receptor repertoire analyses suggested that exFoxp3 cells develop from both natural and adaptive T(reg) cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.