Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo

The stability of expression of the transcription factor Foxp3 in vivo has not been thoroughly assessed. Bluestone and colleagues find that Foxp3 expression can be unstable and that cells that lose Foxp3 expression can assume a proinflammatory autoaggressive phenotype. Regulatory T cells (Treg cells) are central to the maintenance of immune homeostasis. However, little is known about the stability of Treg cells in vivo. In this study, we demonstrate that a substantial percentage of cells had transient or unstable expression of the transcription factor Foxp3. These 'exFoxp3' T cells had an activated-memory T cell phenotype and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers were higher in inflamed tissues in autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid onset of diabetes. Finally, analysis of the T cell receptor repertoire suggested that exFoxp3 cells developed from both natural and adaptive Treg cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.