Double-edged Gadd45

On page 1341, Liu and colleagues report that members of the growth arrest and DNA damage-inducible (Gadd45) family help both start and stop effector T cell activity—critically acting to quench autoimmune T cells gone haywire.The Gadd45 family is best known and named for arresting growth of stressed cells by binding cell cycle machinery. In immune cells, the Gadd45 proteins directly bind MEKK4, promoting its activation of the p38 and JNK MAP kinases. Gadd45β and Gadd45γ's activation of p38 is essential for jump-starting T helper (Th) type 1 cell differentiation via production of interferon-γ (IFNγ).

Previously, this group demonstrated that mice lacking Gadd45β mount a much reduced Th1 response against intracellular pathogens like Listeria monocytogenes. The diminished IFNγ-producing cells suggested that Gadd45β helps T cells differentiate. But now their recent studies suggest an additional function in termination of activated Th1 cells. A balance between initiation and termination is critical for controlling Th cell numbers.

Thus, the authors hypothesized that Gadd45β and Gadd45γ might control both Th1 initiation and death. They found that Gadd45β-deficient T cells took a bit longer to initiate. However, once activated, the cells divided more times and were more resistant to cell death than wild-type T cells.

In a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, Gadd45β knock-out mice suffered from a delayed, but prolonged T cell attack on the brain compared with wild-type mice. This effect was specific to the Gadd45β-deficient T cells. Mice lacking both Gadd45β and Gadd45γ developed spontaneous systemic autoimmune disorders.

These data suggest that the Gadd45 proteins are required to initiate an effective Th1 response against certain pathogens but also to terminate the Th1 response and avoid autoimmune disease. How the Gadd45 proteins control both initiation and termination may depend on different p38 substrates present in naive Th cells versus mature Th1 cells. At this point, says senior author Binfeng Lu, “that's pure speculation.”