Deficiency of indoleamine 2,3-dioxygenase in donor bone marrow cells leads to exacerbation of graft-versus-host disease through enhanced generation of neutrophils and effector T cells (TRAN2P.965)

Abstract

Abstract Indoleamine 2,3-dioxygenase-1 (IDO-1) is a tryptophan metabolic enzyme expressed by various types of cells including dendritic cells, myeloid-derived suppressor cells, and intestinal epithelial cells. The enzyme is also well known for immune suppressive function, while the underlying mechanism is still obscure. To understand cellular mechanism underlying the suppressive role of IDO-1, especially expressed by donor-derived myeloid cells in generation of graft-versus-host disease (GVHD), we transplanted T cell-depleted (TCD) BM cells from Ido-1-/- mice together with wild type (WT) T cells on C57BL/6 (B6) background into MHC-matched allogeneic BALB.B mice. Compared with BALB.B hosts that received WT TCD-BM and T cells, those of Ido-1-/- TCD-BM and WT T cells showed exacerbated GVHD. T cell frequencies in blood and target organs, and their productions of effector cytokines (IFN-γ- and IL-17) were enhanced in the recipients of Ido-1-/- TCD-BM, compared with those of WT TCD-BM. Generation of CD11b+Gr-1+ cells, especially of Ly6GhiLy6lo cells, was also enhanced in the formers. The CD11b+Gr-1+ cells originated from Ido-1-/- TCD-BM exerted lower suppressive activity over proliferation and cytokine production of co-incubated allo-reactive T cells. Proportions of CD244- neutrophils within the Ly6GhiLy6lo population of Ido-1-/- TCD-BM origin were significantly higher than that of WT TCD-BM. These results demonstrate implication of IDO-1 function in neutrophil generation.