Interactions Between DC And T-Cells Initiate Counter-Regulatory Immune Activities That Limits Amplification Of Allo-Immune Responses And GvHD
Year: 2009
Type: article
Abstract: Acute graft-versus-host disease (GvHD) remains a major complication following allogenic hematopoietic stem cell transplant (HSCT). Our reports and several publications have suggested a potential beneficial effect of donor DC during HSCT. Using allogeneic MHC-mismatched HSCT mice model, we previously demonstrated that recipients transplanted with FACS-purified CD11b- DC with HSC and T-cells had increased GvL and limited GvHD. In the current study, we found that transplantation of T-cells from IFN-γ knock-out mice resulted in severe GvHD and higher levels of Th17 cells compared with recipients of T-cells from wide-type (WT) mice, suggesting that donor T-cell synthesis of IFN-γ induced by donor DC is necessary to augment expansion of allo-reactive T-cells that mediate GvL while subsequently limiting generalized activation of donor T-cells that lead to off-target effects and GvHD. In order to further clarify the mechanisms involved in the action of donor DC on the limitation of GvHD, we detected the level of the IFN-γ-inducible indoleamine-2,3-dioxygenase(IDO) protein, which has been reported to exert inhibitory effects on T cells activity, on donor DCs and its potential roles in regulating donor T cell allo-immune activity. We set up an in vitro co-culture system including purified CD11b- DC from WT or IDO knock-out mice and CFSE-labeled syngeneic T cells in the presence of allogeneic antigen. T-cells co-cultured with CD11b- DC had higher proliferation rates compared with T-cells cultured with allo-antigen in the absence of DCs. Furthermore, CD8 T-cells proliferated earlier and more than CD4 T-cells in response to alloantigen in the presence of CD11b- DC, suggesting CD8 T-cells be mainly responsible for the observed GvL activity in murine model systems. IDO expression on WT CD11b- DC was increased in 3–7 day cultures containing syngeneic T cells and allo-antigen but not on DC cultured with allo-antigen alone. Thus, IFN-γ-induced IDO expression on CD11b- donor DCs might be a critical downstream event that inhibits continued T-cell activation by initiating counter-regulatory immune activities that limit allo-immune responses. Interestingly, T cells co-cultured with CD11b+ DC from IDO knock-out donors had higher proliferation rate than T cells co-cultured with CD11b- DC on day-7. Further studies using IDO knock-out mice as DC donors in our C57BL/6→B10.BR transplant model are essential to understand the role of IDO expression of DC in allogeneic HSCT.
Authors: Y. Lu, J.-M. Li, W. Harris, E. Waller
Institutions: Emory University, Winship Cancer Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2081400838