Differential effect of DJ-1/PARK7 on development of natural and induced regulatory T cells

Abstract

Regulatory T cells (Tregs) are essential for maintaining an effective immune tolerance and a homeostatic balance of various other immune cells. To manipulate the immune response during infections and autoimmune disorders, it is essential to know which genes or key molecules are involved in the development of Tregs. Transcription factor Foxp3 is required for the development of Tregs and governs most of the suppressive functions of these cells. Inhibited PI3K/AKT/mTOR signalling is critical for Foxp3 stability. Previous studies have suggested that DJ-1 or PARK7 protein is a positive regulator of the PI3K/AKT/mTOR pathway by negatively regulating the activity of PTEN. Thus, we hypothesised that a lack of DJ-1 could promote the development of Tregs. As a result, loss of DJ-1 decreased the total CD4 + T cell numbers but increased the fraction of thymic and peripheral nTregs. In contrast, Foxp3 generation was not augmented following differentiation of DJ-1-deficient naïve CD4 + T cells. DJ-1-deficient-iTregs were imperfect in replication, proliferation and more prone to cell death. Furthermore, DJ-1 deficient iTregs were less sensitive to pSmad2 and pStat5 signalling but had activated AKT/mTOR signalling. These observations reveal an unexpected differential role of DJ-1 in the development of nTregs and iTregs.