Roli Khattri

An essential role for Scurfin in CD4+CD25+ T regulatory cells.

The molecular properties that characterize CD4+CD25+ regulatory T cells (TR cells) remain elusive. Absence of the transcription factor Scurfin (also known as forkhead box P3 and encoded by Foxp3) causes a rapidly fatal lymphoproliferative disease, similar to that seen in mice lacking cytolytic T lymphocyte–associated antigen 4 (CTLA-4). Here we show that Foxp3 is highly expressed by TR cells and is associated with TR cell activity and phenotype. Scurfin-deficient mice lack TR cells, whereas mice that overexpress Foxp3 possess more TR cells. In Foxp3-overexpressing mice, both CD4+CD25− and CD4−CD8+ T cells show suppressive activity and CD4+CD25− cells express glucocorticoid-induced tumor-necrosis factor receptor–related (GITR) protein. The forced expression of Foxp3 also delays disease in CTLA-4−/− mice, indicating that the Scurfin and CTLA-4 pathways may intersect and providing further insight into the TR cell lineage.

The Amount of Scurfin Protein Determines Peripheral T Cell Number and Responsiveness

In the absence of the recently identified putative transcription factor scurfin, mice develop a lymphoproliferative disorder resulting in death by 3 wk of age from a pathology that resembles TGF-β or CTLA-4 knockout mice. In this report, we characterize mice that overexpress the scurfin protein and demonstrate that these animals have a dramatically depressed immune system. Mice transgenic for the Foxp3 gene (which encodes the scurfin protein) have fewer T cells than their littermate controls, and those T cells that remain have poor proliferative and cytolytic responses and make little IL-2 after stimulation through the TCR. Although thymic development appears normal in these mice, peripheral lymphoid organs, particularly lymph nodes, are relatively acellular. In a separate transgenic line, forced expression of the gene specifically in the thymus can alter thymic development; however, this does not appear to affect peripheral T cells and is unable to prevent disease in mice lacking a functional Foxp3 gene, indicating that the scurfin protein acts on peripheral T cells. The data indicate a critical role for the Foxp3 gene product in the function of the immune system, with both the number and functionality of peripheral T cells under the aegis of the scurfin protein.