G Protein-Coupled Receptor 83 Overexpression in Naive CD4 super(+)CD25 super(-) T Cells Leads to the Induction of Foxp3 super(+) Regulatory T Cells In Vivo

Foxp3 functions as a lineage specification factor for the development of naturally occurring thymus-derived CD4 super(+)CD25 super(+) regulatory T (Treg) cells. Recent evidence suggests that naive Foxp3 super(-)CD4 super(+)CD25 super(-) T cells can be converted in the periphery into Foxp3 super(+) Treg cells. In this study, we have identified the G protein-coupled receptor (GPR)83 to be selectively up-regulated by CD4 super(+)CD25 super(+) Treg cells of both murine and human origin in contrast to naive CD4 super(+)CD25 super(-) or recently activated T cells. Furthermore, GPR83 was induced upon overexpression of Foxp3 in naive CD4 super(+)CD25 super(-) T cells. Transduction of naive CD4 super(+)CD25 super(-) T cells with GPR83-encoding retroviruses did not confer in vitro suppressive activity. Nevertheless, GPR83-transduced T cells were able to inhibit the effector phase of a severe contact hypersensitivity reaction of the skin, indicating that GPR83 itself or GPR83-mediated signals conferred suppressive activity to conventional CD4 super(+) T cells in vivo. Most strikingly, this in vivo acquisition of suppressive activity was associated with the induction of Foxp3 expression in GPR83-transduced CD4 super(+) T cells under inflammatory conditions. Our results suggest that GPR83 might be critically involved in the peripheral generation of Foxp3 super(+) Treg cells in vivo.