On page 565, Haxhinasto et al. pinpoint the signaling roadblock that stops CD4+ T cells from turning into regulatory T (T reg) cells.

Some T reg cells develop directly from thymic progenitor cells, but others seem to be converts that were once CD4+ T cells. These potentially inflammatory CD4+ T cells turn into immune-suppressing T reg cells when they simultaneously bind antigen and the cytokine TGF-â. The mechanism that flips this switch was unknown.

T reg cells have less PI3K/Akt signaling, which promotes T cell proliferation and survival. The authors now find that the suppression of Akt allows CD4+ T cells to convert. Activated CD4+ T cells that were forced to express Akt were unable to turn on T reg cell–specific genes, including the transcription factor Foxp3. The expression of Akt did not, however, prevent the development of T reg cells from immature thymic T cells that had already turned on Foxp3. Foxp3 levels in these T reg cells were stable, perhaps because the gene becomes fixed in an active state by chromatin modifications.

The perpetual activation of Akt leads to overactive T cells that can trigger autoimmunity and the rejection of transplanted organs. Blockade of Akt signaling using the drug rapamycin can prevent organ rejection. The group found that activated, rapamycin-treated CD4+ T cells expressed Foxp3 and other T reg cell–specific genes, suggesting that the drug helps replace offensive T cells with defensive T reg cells.