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

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Abstract
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 β signaling played a minor role in the generation and subsequent differentiation of these T reg precursor cells.