Donor Vγ4+T cells promote graft-versus-leukemia effect and ameliorate acute graftversus- host disease in allogeneic hematopoietic stem cell transplantation

Abstract

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most effective ways of treating leukemia and other malignant diseases. However, disease recurrence and GVHD are still the major causes of death after allo-HSCT. Previous studies showed that immune cells involved in graft versus leukemia (GVL) effect traditionally include CD8+ T, CD4+ T and NK cells. Unfortunately, some of these T-cell subsets also cause graft-versus- host disease (GVHD). The role of donor γδT cells after transplantation is less well defined. We detected direct anti-leukemia cytotoxicity of γδT cells in vitro and the cytotoxicity of Vγ1 subset was stronger than the Vγ4 subset. To evaluate the role of donor γδT cells in aGVHD and GVL, we established the murine HLA fully mismatched allo-HSCT GVL/GVHD model. Our results showed that TCRδ−/− donor bone marrow cells caused enhanced disease progression and aggravated aGVHD compared with wildtype donors. Furthermore, flow cytometry analysis demonstrated γδT cells mediated anti-leukemia effects through promoting IFN-γ production by CD8+ T cells while suppressed aGVHD by inhibiting the activation of CD4+ T cells in liver, lung and IEL. The experiments of adoptive transfer of in vitro expanded γδT/Vγ1/Vγ4 cells and the in vivo depletion of Vγ1/Vγ4 cells indicated that the subset of donor γδT cells to alleviate murine aGVHD and enhance GVL effect might be Vγ4 γδT cells. The GVL effect of Vγ4 cells in vivo could be mediated by the production of IL-17A and regulation of CD8+ T cell function. These findings suggest donor γδT cells infusion could be a novel strategy to improve patients’ overall survival after allo-HSCT.