Identification and characterization of Foxp3+ γδ T cells in mouse and human

Regulatory T cells (Tregs) expressing TCRαβ 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+TCRαβ+ Tregs can be generated from mouse and human CD4+CD25− T cells in vitro via TGF-β induction. As growing evidences suggest that γδ T cells also have immunoregulatory function, we have attempted to identify and characterize Foxp3+ cells in mouse and human γδ T cells. We found that freshly isolated mouse splenic γδ T cells did not express Foxp3. When mouse splenocytes were stimulated with anti-TCRγδ in the presence of TGF-β, a population of Foxp3+ γδ T cells appeared, in most of which expressed CD25 as well. Compared with CD25− γδ T cells, TGF-β induced CD25+ γδ T cells not only expressed Foxp3, but also had increased TGF-β and GITR expression. Furthermore, the TGF-β induced γδ 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 γδ T cells expressed Foxp3, similar culture condition with anti-TCRγδ plus TGF-β failed to generate functional human Foxp3+ γδ T cells. In conclusion, our results suggest that mouse splenic Foxp3+ γδ T cells with suppressive function can be induced by TCR and TGF-β costimulation, whereas functional human Foxp3+ γδ T cells in peripheral blood could not be generated under the same condition.