Identification of an immediate Foxp3− precursor to Foxp3+ regulatory T cells in peripheral lymphoid organs of nonmanipulated mice

CD4(+)CD25(+) regulatory T cells (T reg cells) expressing the transcription factor Foxp3 can be induced from peripheral T cell receptor (TCR) transgenic CD4(+)CD25(-)Foxp3(-) T cells stimulated with noninflammatory dendritic cells presenting low amounts of agonist cognate antigen. However, limited evidence exists for extra-thymic T reg cell generation from non-TCR transgenic T cells in unmanipulated mice. We compared events early during agonist-driven generation of Foxp3(+) TCR transgenic T cells to polyclonal CD4(+) T cell populations in unmanipulated mice. We identified an interleukin-2- and phosphatidylinositol-3-kinase-dependent precommitted Foxp3(-) precursor to Foxp3(+) T reg cells in peripheral lymphoid organs. Transforming growth factor beta signaling played a minor role in the generation and subsequent differentiation of these T reg precursor cells.