In the past years there has been a search for mechanisms of defective T cell regulation in human autoimmunity. Although data from the site of inflammation are limited, it is now clear that immune regulatory mechanisms such as Treg are present in high numbers in the inflamed synovium. The question is why these cells are unable to control the local inflammation. We have recently shown that Treg from inflamed joints of JIA patients are fully functional, but fail to control CD4 and CD8 effector T cell (Teff) proliferation and cytokine production, due to resistance of Teff to suppression (Wehrens, Blood. 2011 Sep 29;118(13):3538-48). The resistance of Teff to suppression was caused by hyperactivation of PKB/c-AKT in Teff, and could be partially induced by TNF-α and IL-6. These data suggest that for a Treg enhancing strategy to be successful in the treatment of autoimmune inflammation, resistance due to PKB/c-akt hyperactivation should be targeted as well.