Conversion of CD4(+) CD25(−) cells into CD4(+) CD25(+) regulatory T cells in vivo requires B7 costimulation, but not the thymus

The CD4(+) CD25(+) regulatory T cells play a critical role in controlling autoimmunity, but little is known about their development and maintenance. In this study, we investigated whether CD4(+) CD25(−) cells can convert to CD4(+) CD25(+) regulatory T cells in vivo under natural conditions. CD4(+) CD25(−) cells from CD45.1(+) mice were sorted and transferred into congenic CD45.2(+) mice. Converted CD4(+) CD25(+) cells could be detected in lymphoid organs as early as 1 wk after transfer and by 6 wk after transfer, 5–12% of transferred CD4(+) cells expressed CD25. Converted CD4(+) CD25(+) cells themselves failed to proliferate after stimulation, but could suppress proliferation of responder cells in vitro, and also expressed high levels of Foxp3 mRNA. In addition, CD4(+) CD25(−) cells transferred into thymectomized congenic mice converted to CD4(+) CD25(+) cells that also suppressed responder cell proliferation in vitro, and expressed high levels of Foxp3 mRNA. Finally, CD4(+) CD25(−) cells transferred into B7(−/−) mice failed to convert into CD4(+) CD25(+) cells that exhibit the regulatory phenotype. These data indicate that CD4(+) CD25(−) cells convert into CD4(+) CD25(+) regulatory T cells spontaneously in vivo and suggest that this conversion process could contribute significantly to the maintenance of the peripheral CD4(+) CD25(+) regulatory T cell population.