OPINION ARTICLE published: 05 July 2012 doi: 10.3389/fimmu. 2012.00191 deficient Tregs were fully functional in vitro and in vivo, essentially indistinguishable from wild type Tregs (Pillai et al., 2011). Thus, they seemed to have gained rather than lost function. Subsequent analysis revealed that the loss of IL-10 and IL-35 was compensated for by the concurrent increase in cathepsin E (CTSE) expression. This appeared to be required to facilitate the expression and/or release of TRAIL, a member of the TNF superfamily that can mediate apoptosis, programmed necrosis (necroptosis) or suppress proliferation via its surface bound form or as a soluble trimer (Wang and el-Deiry, 2003; Schaefer et al., 2007). Importantly, this rendered IL-10/IL-35 double-deficient Tregs functionally dependent on TRAIL in vitro and in vivo (Pillai et al., 2011). These data highlight two important concepts. First, the loss of certain regulatory mechanisms may result in unforeseen molecular changes which facilitate functional compensation by the upregulation of another inhibitory mechanism. Second, this study revealed that unappreciated cross-regulatory pathways may exist which control the utilization of certain suppressive mechanisms. Collectively this may serve to facilitate Treg functional plasticity. Whether such mechanisms operate in vivo in the absence of genetic manipulation remains to be determined. However, it is possible that the mechanisms that are dominant differ in Tregs from different genetic backgrounds. Indeed, TRAIL is not a major mechanism used by C57BL/6 Tregs, which express low levels of CTSE, but may be a more dominant mechanism used by Balb/c Tregs, which coincidentally express high levels of CTSE (Pillai et al., 2011). Additional studies will clearly be required to determine the prevalence of Treg functional plasticity caused by divergent genetic backgrounds and/or altered environmental circumstances.