Graft plasmacytoid dendritic cells improve thymic function in allogeneic hematopoietic cell transplantation

Abstract

Abstract Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is a well established cure for a variety of hematologic diseases. However, graft-versus-host disease(GVHD) remain the primary obstacles to successful transplant. GVHD results from donor T-cell recognition of a genetically disparate recipient. Thymus has been recognized as a recipient tissue that can be severely damaged by GVHD. Plasmacytoid dendritic cells(pDCs) is a distinct subset of DC, which have both immunogenic and tolerogenic effect in allo-HSCT, licensed by the microenvironment to respond to the milieu in which they migrate. Impaired thymic DC has been the major causation of dysfunctional thymic negative selection, thus generating allo-reactive T cells and GVHD. To further demonstrate pDCs from the graft are migrating to thymus to protecting host from GVHD. We transplanted B10.BR mouse with pDCs from MHC mismatched GFP-labeled C57/B6 mouse, along with hematopoietic stem cells and T-cells from normal C57/B6 mouse. The results from the confocal imaging suggest that pDCs are migrating to thymus 14 days after allo-HSCT. CCR9 expression is important for pDCs migrating to thymus. We transplated mice with either wild type pDCs or CCR9 knock out pDCs. Survival rate is significantly lower in group transplanted with CCR9-knockout pDCs suggesting thymus is a critical place for pDCs to induce tolerogenic response. We also tranplanted wild tipe pDCs with thymectomized host and normal host. Thymectomy group have better survival rate compared to non-thymectomized group, further confirming the association between pDCs and thymus. Improved thymic function post transplant with pDCs from the graft may have a potential to decrease GVHD.