Conversion of Peripheral CD4⁺CD25⁻ Naive T Cells to CD4⁺CD25⁺ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3

CD4⁺CD25⁺ regulatory T cells (T_reg) are instrumental in the maintenance of immunological tolerance. One critical question is whether T_reg can only be generated in the thymus or can differentiate from peripheral CD4⁺CD25⁻ naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4⁺CD25⁻ T cells into anergic/suppressor cells that are CD25⁺, CD45RB^−/low and intracellular CTLA-4⁺ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor β (TGF-β). Although transcription factor Foxp3 has been shown recently to be associated with the development of T_reg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-β induced Foxp3 gene expression in TCR-challenged CD4⁺CD25⁻ naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-β and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-β–converted transgenic CD4⁺CD25⁺ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4⁺ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-β–induced suppressor T cells prevented house dust mite–induced allergic pathogenesis in lungs.