Identification and characterization of Foxp3(+) gammadelta T cells in mouse and human

Regulatory T cells (Tregs) expressing TCRalphabeta play a critical role in the maintenance of the immune system homeostasis. Tregs express the cell surface markers CD4 and CD25 as well as the transcription factor Foxp3. Foxp3(+)CD4(+)CD25(+)TCRalphabeta(+) Tregs can be generated from mouse and human CD4(+)CD25(-) T cells in vitro via TGF-beta induction. As growing evidences suggest that gammadelta T cells also have immunoregulatory function, we have attempted to identify and characterize Foxp3(+) cells in mouse and human gammadelta T cells. We found that freshly isolated mouse splenic gammadelta T cells did not express Foxp3. When mouse splenocytes were stimulated with anti-TCRgammadelta in the presence of TGF-beta, a population of Foxp3(+) gammadelta T cells appeared, in most of which expressed CD25 as well. Compared with CD25(-) gammadelta T cells, TGF-beta induced CD25(+) gammadelta T cells not only expressed Foxp3, but also had increased TGF-beta and GITR expression. Furthermore, the TGF-beta induced gammadelta T cells mediated a potent immunosuppressive effect on anti-CD3 stimulated T cell activation and proliferation. In contrast, although a small fraction of human peripheral blood and tumor infiltrating gammadelta T cells expressed Foxp3, similar culture condition with anti-TCRgammadelta plus TGF-beta failed to generate functional human Foxp3(+) gammadelta T cells. In conclusion, our results suggest that mouse splenic Foxp3(+) gammadelta T cells with suppressive function can be induced by TCR and TGF-beta costimulation, whereas functional human Foxp3(+) gammadelta T cells in peripheral blood could not be generated under the same condition.