Unexpected role of TNF-α in graft versus host reaction (GVHR): Donor-derived TNF-α suppresses GVHR via inhibition of IFN-γ -dependent donor type-1 immunity

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation, leading to significant morbidity and mortality. Host-derived TNF-α play a role in the induction of allo-reactive donor T cell activation and the pathogenesis of GVHD. On the other hand, the precise role of donor-derived TNF-α in GVHD remains unclear. To elucidate this issue, we designed an acute GVHD model using (B6×D2) F1 recipient mice transferred with spleen cells derived from either wild-type or TNF-α^-/- C57BL/6 mice. Surprisingly, we found that spleen cells from TNF-α^-/- mice induce more severe graft versus host reaction (GVHR) than wild-type spleen cells upon transfer into B6D2F1 mice. Transplantation of TNF-α^-/- mouse spleen cells was associated with enhanced anti-host CTL generation and augmented deletion of host cells. Moreover, mice receiving TNF-α^-/- cells showed significantly higher levels of serum IFN-γ, which was mainly produced by donor CD8⁺ T cells. We also demonstrated that TNF-α deficiency in donor spleen cells caused a marked elevation of TNF-α producing capacity by LPS-stimulated host macrophages. Such enhanced GVHR was completely prevented by using TNF-α^-/-TNF-γ^-/- splenic cells. Our findings demonstrate, for the first time, that donor-derived TNF-α suppress GVHR by inhibiting IFN-γ -dependent donor type-1 immunity which is essential for host TNF-α elevation.