Inhibition of clonal expansion by Foxp3 expression as a mechanism of controlled T-cell responses and autoimmune disease.

The essential role of the transcription factor Foxp3 in the development and function of Treg has been well documented. The role of Foxp3 in non-Treg, however, is not fully understood. Emerging evidence indicates that Foxp3 expression is not confined to CD4(+) CD25(+) Treg. The present study shows that in Foxp3 transgenic (Foxp3-Tg) mice, in which the transgene is driven by the lck distal promoter, CD4(+)CD25(-) T cells that express the Foxp3 transgene do not upregulate the expression of CD25(-), GITR, or CTLA-4, and do not have suppressive function; however, the Foxp3-Tg(+)CD4(+)CD25(-) T cells exhibit significantly reduced proliferative response to TCR engagement. Foxp3-Tg mice are resistant to collagen-induced arthritis via reduced cellular proliferation of activated T cells. These findings indicate that Foxp3 upregulation in activated non-Treg may be a mechanism to suppress immune responses by reduced clonal expansion of activated T cells.