Leading role for FOXP3

The programmed differentiation of CD4⁺ T helper (T_H) cells into distinct effector lineages seems to be controlled by two key genes, T-bet and GATA3, which encode transcription factors that are essential for T_H1- and T_H2-cell development, respectively. Now, researchers have identified what might be the equivalent master gene for the development of CD4⁺ regulatory T (T_Reg) cells.

Recently, the human disease IPEX (immune dysregulation, polyendocrinopathy and entereropathy, X-linked) and its mouse counterpart, the Scurfy mutation, were found to be caused by mutations in the FOXP3 (forkhead box P3) gene, which encodes a forkhead/winged-helix transcription factor. Shimon Sakaguchi and his team were struck by the similarities between IPEX syndrome and the multi-organ autoimmunity that occurs in mice that are deficient for the naturally occurring CD4⁺CD25⁺ population of T_Reg cells, and they wondered if FOXP3 is involved in the development of these cells.

In support of this hypothesis, they found that Foxp3 is expressed predominantly by CD4⁺CD25⁺ T cells. Next, they tested whether forced expression of Foxp3 could turn a naive T cell into a T_Reg cell. Peripheral CD4⁺CD25⁻ T cells from normal mice were induced to express Foxp3 by retroviral transduction. Similar to prototypical T_Reg cells, the Foxp3-expressing cells proliferated poorly and secreted little interleukin-2 (IL-2), interferon-γ, IL-4 or IL-10 in response to T-cell receptor stimulation. Moreover, the Foxp3-transduced T cells expressed higher levels of T_Reg-cell-associated molecules, such as CD25, CTLA4, GITR and CD103, than the non-transduced cells.

But, can the Foxp3-transduced T cells actually regulate immune responses? In vitro, these cells inhibited the proliferation of non-transduced T cells and, similar to naturally occurring CD25⁺CD4⁺ T_Reg cells, this suppression required cell–cell contact.

However, the true test of a T_Reg cell is whether it can suppress autoimmune and inflammatory diseases in vivo. If lymphocyte-deficient mice are reconstituted with CD4⁺CD25⁻ T cells only, they develop severe autoimmune gastritis and inflammatory bowel disease, which can be prevented by the co-transfer of naturally occurring CD4⁺CD25⁺ T_Reg cells. Similarly, Foxp3-transduced T cells were found to prevent disease, which indicates that expression of Foxp3 can convert a naive T cell into a fully fledged regulator.

This study supports the idea that FOXP3 is an essential instructor of CD4⁺CD25⁺ T_Reg-cell development, which is of importance both practically, as FOXP3 could be the first specific marker of T_Reg cells, and clinically, as it provides a potential target for the therapeutic manipulation of CD4⁺CD25⁺ T_Reg cells.