The Plasticity of Regulatory T Cell Function

Abstract

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.