Shimon Sakaguchi and colleagues at Kyoto University in Japan, and Alexander Rudensky and colleagues at the Howard Hughes Medical Institute at the University of Washington, Seattle, both showed that a forkhead transcription factor Foxp3 is the essential element in creating T_R cells. Sakaguchi, at #5, beat Rudensky, at #7, to the punch by a matter of weeks, but the two teams used essentially similar methods.

The starting observation is that in animal models a reduction in T_R cells is associated with various organ-specific autoimmune diseases, such as thyroiditis, gastritis, and type 1 diabetes. In humans, some genetic diseases that are associated with autoimmune problems have an imbalance in the T_R cells. A mutant mouse strain, called scurfy, which exhibits similar autoimmune symptoms, and the human genetic diseases, both show mutations in Foxp3. So, does Foxp3 actually regulate the development of T_R cells, or is it merely associated with their functioning?

T_R cells seem to be created both in the thymus and in the periphery. Sakaguchi’s group looked at the mRNA being made by immature T cells in the thymus. Those that expressed the CD25 marker associated with T_R cells also expressed Foxp3 mRNA, while other immature T cells did not. However, the T cells are not merely making Foxp3 in response to activation, because stimulating those cells with self antigens did not affect the level of Foxp3 expression. However, putting an active Foxp3 gene into naïve T cells turned those cells into ones that responded almost exactly like natural T_R cells. In vitro they suppressed T cells active against self antigens. And in a mouse model of inflammatory bowel disease and autoimmune gastritis, T cells with Foxp3 were as effective as natural T_R cells in preventing the symptoms of disease.

Sakaguchi’s paper thus goes a very long way towards establishing that Foxp3 is an essential master gene that controls the development of T_R cells. Rudensky’s adds some additional evidence. In addition to showing that T_R cells express Foxp3, Rudensky’s group deleted the gene in mice and showed that these mice both succumb to disease almost indistinguishable from that of the natural scurfy mutants and lack T_R cells. Giving natural T_R cells to Foxp3-deficient mice prevents disease, showing that the lack of Foxp3 is associated with a lack of T_R cells.

The therapeutic implications of this work are far-reaching. For autoimmune diseases it might be possible to harvest T cells specific to self antigens and turn them into T_R cells by transfecting them with Foxp3. Transplant rejection could likewise be controlled by creating appropriately targeted T_R cells. Sakaguchi calls these "made-to-order regulatory T cells." Decreasing the number or activity of T_R cells, perhaps by blocking Foxp3, might help the body to reject tumors and could boost the effectiveness of vaccines.