The plasticity of regulatory T cell function

Regulatory T cells (T _regs) can suppress a wide variety of cell types, in diverse organ sites and inflammatory conditions. Whereas T _regs possess multiple suppressive mechanisms, the number required for maximal function is unclear. Furthermore, whether any interrelationship or cross-regulatory mechanisms exist to orchestrate and control their utilization is unknown. In this study, we assessed the functional capacity of T _regs lacking the ability to secrete both IL-10 and IL-35, which individually are required for maximal T _reg activity. Surprisingly, IL-10/IL-35 double-deficient T _regs were fully functional in vitro and in vivo. Loss of IL-10 and IL-35 was compensated for by a concurrent increase in cathepsin E (Ctse) expression, enhanced TRAIL (Tnfsf10) expression, and soluble TRAIL release, rendering IL-10/IL-35 double-deficient T _regs functionally dependent on TRAIL in vitro and in vivo. Lastly, whereas C57BL/6 T _regs are normally IL-10/IL-35 dependent, BALB/c T _regs, which express high levels of cathepsin E and enhanced TRAIL expression, are partially TRAIL dependent by default. These data reveal that cross-regulatory pathways exist that control the utilization of suppressive mechanisms, thereby providing T _reg functional plasticity.