The Role of Foxp3 in Regulatory T Cell Differentiation and Function

Naturally occurring regulatory T (Treg) cells represent a distinct lineage of T lymphocytes that play a role in the regulation of immune responses and in the maintenance of peripheral tolerance. The discovery of Foxp3 as a key transcription factor selectively expressed in Treg cells enabled phenotypically defined populations of these cells to be identified and characterised. Here, we review the role of Foxp3 in the differentiation and function of Treg. Genetic Treg deficiency due to Foxp3-null mutations leads to systemic autoimmunity both in mice and humans. Earlier studies reported Foxp3 expression to be specific for Treg, designating Foxp3 as the ‘regulatory T cell lineage specification factor’. However, recent observations challenge these views and implicate factors other than Foxp3 in Treg development. Whilst high and stable Foxp3 expression levels may be required to maintain the Treg cell phenotype and function, Treg lineage commitment might be independent of Foxp3. Further complexity is likely given the identification of novel Foxp3 splice variants in Treg cells; these may alter the functional outcomes of expression of this molecule.