Molecular mechanisms of regulatory T cell development

CD4(+)CD25(+) natural regulatory T (nT(R)) lymphocytes represent a distinct thymus-derived T cell lineage that serves to establish immunological tolerance in the periphery. The discovery of Foxp3 as a transcription factor essential to the differentiation of CD4(+)CD25(+) T(R) cells enabled detailed studies into the molecular mechanisms of T(R) cell development, peripheral homeostasis, and effector functions.

Comparative analysis of Foxp3(+) nT(R) cells and nT(R) cell precursors expressing a functionally inactive Foxp3 mutant protein indicated that while Foxp3 is not essential for nT(R) cell development in the thymus, it is critical to the peripheral homeostasis and suppressor functions of nT(R) cells. A second subset of Foxp3(+) regulatory T cells can be induced de novo from conventional CD4(+) Foxp3(-) T cells both in vitro, upon antigenic stimulation in the presence of transforming growth factor beta and interleukin-2, and in vivo. Like nT(R) cells, the induced regulatory T (iT(R)) cells are also dependent on Foxp3 expression for their suppressor function. It is likely that nT(R) and iT(R) cells serve nonredundant functions in the maintenance of immunological tolerance.