Functional plasticity in human FOXP3(+) regulatory T cells: implications for cell-based immunotherapy

CD4(+) regulatory T (T(reg)) cells expressing the Foxp3 transcription factor are critical for the induction and maintenance of immune homeostasis and self-tolerance in experimental rodents and humans. Foxp3(+) T(reg) cells constitute a unique CD4(+) T cell subset with potent suppressive properties, and their functional and homeostatic stability is essential to ensure dominant tolerance in a variety of inflammatory settings. Interestingly, recent evidence points to the inherent potential of T(reg) cells to adapt to environmental cues and consequently manifest functional plasticity by downregulating Foxp3 expression, and reprogramming into inflammatory T cells. The potential for suppressive Foxp3(+) T(reg) cells to undergo functional plasticity and gain inflammatory properties is of concern when one considers the ex vivo manipulation or generation of such cells for therapeutic purposes in various autoimmune or chronic inflammatory disorders. Collectively, the experimental evidence accumulated so far on the modalities of this plasticity can provide valuable cues as to strategies that can be implemented to control it, potentially allowing to facilitate the path to efficient and safe T(reg)-based therapy.