Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10

CD4(+) regulatory T cells (T(reg) cells) that produce interleukin 10 (IL-10) are important contributors to immune homeostasis. We generated mice with a 'dual-reporter' system of the genes encoding IL-10 and the transcription factor Foxp3 to track Treg subsets based on coordinate or differential expression of these genes. Secondary lymphoid tissues, lung and liver had enrichment of Foxp3(+) IL-10-T(reg) cells, whereas the large and small intestine had enrichment of Foxp3+ IL-10(+) and Foxp3(-)IL-10(+) T(reg) cells, respectively. Although negative for II10 expression, both Foxp3(+) and Foxp3(-)CD4(+) thymic precursor cells gave rise to peripheral IL-10(+) T(reg) cells, with only Foxp3-precursor cells giving rise to all Treg subsets. Each T(reg) subset developed in IL-10-deficient mice, but this was blocked by treatment with antibody to transforming growth factor-beta. Thus, Foxp3(+) and Foxp3 precursor cells give rise to peripheral IL-10-expressing Treg cells by a mechanism dependent on transforming growth factor-beta and independent of IL-10.