Adoptive transfer of allogeneic T cells can lead to elimination of leukemic cells via graft-versus-leukemia reactivity, however, these cells may also cause potentially deadly graft-versus-host disease (GVHD). Ramadan et al. found that human or murine T9 cells (CD4+ and CD8+ cells differentiated under IL-4 and TGFβ) activated with IL-33 upregulate mST2, IL-9, PU.1, and amphiregulin expression, significantly reducing the severity of GVHD in mice. At the same time, T9IL-33 cells show enhanced CD8α expression for better killing of leukemia.
Allogeneic immune cells, particularly T cells in donor grafts, recognize and eliminate leukemic cells via graft-versus-leukemia (GVL) reactivity, and transfer of these cells is often used for high-risk hematological malignancies, including acute myeloid leukemia. Unfortunately, these cells also attack host normal tissues through the often fatal graft-versus-host disease (GVHD). Full separation of GVL activity from GVHD has yet to be achieved. Here, we show that, in mice and humans, a population of interleukin-9 (IL-9)-producing T cells activated via the ST2-IL-33 pathway (T9IL-33 cells) increases GVL while decreasing GVHD through two opposing mechanisms: protection from fatal immunity by amphiregulin expression and augmentation of antileukemic activity compared with T9, T1, and unmanipulated T cells through CD8alpha expression. Thus, adoptive transfer of allogeneic T9IL-33 cells offers an attractive approach for separating GVL activity from GVHD.
