Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment

Abstract

Bone marrow transplantation offers great promise for treating a number of disease states. However, the widespread application of this approach is dependent upon the development of less toxic methods to establish chimerism and avoid graft-versus-host disease (GVHD). CD8+/TCR− facilitating cells (FCs) have been shown to enhance engraftment of hematopoietic stem cells (HSCs) in allogeneic recipients without causing GVHD. In the present studies, we have identified the main subpopulation of FCs as plasmacytoid precursor dendritic cells (p-preDCs). FCs and p-preDCs share many phenotypic, morphological, and functional features: both produce IFN-α and TNF-α, both are activated by toll-like receptor (TLR)-9 ligand (CpG ODN) stimulation, and both expand and mature after Flt3 ligand (FL) treatment. FL-mobilized FCs, most of which express a preDC phenotype, significantly enhance engraftment of HSCs and induce donor-specific tolerance to skin allografts. However, p-preDCs alone or p-preDCs from the FC population facilitate HSC engraftment less efficiently than total FCs. Moreover, FCs depleted of preDCs completely fail to facilitate HSC engraftment. These results are the first to define a direct functional role for p-preDCs in HSC engraftment, and also suggest that p-preDCs need to be in a certain state of maturation/activation to be fully functional.

Induction of FoxP3+CD4+CD25+ regulatory T cells by a bone marrow population distinct from plasmacytoid-DC

“…The FC population has been characterized as having a subset of cells with a phenotype similar to p-preDC [20]. Previous reports have established that p-preDC do not express CD3ε and we have demonstrated that all cells positive for the plasmacytoid-DC marker PDCA-1 reside in the FC-CD3ε − subset [4].…”

“…Results of the current study provide a potential solution to the dichotomy, as there is now evidence that the FC-CD3ε + subset directly induces FoxP3 + CD4 + CD25 + regulatory T cells suggesting that FC-CD3ε + cells have a role in the generation of these T cells following allogeneic SC plus FC transplantation in vivo. It is of interest that although both FC and p-preDC cocultures result in FoxP3 + CD4 + CD25 + regulatory T cell development in vitro, previous studies have demonstrated that p-preDC-mediated allogeneic SC engraftment was significantly less efficient than the FC population [20]. Therefore, not only does the FC-CD3ε + subset have a role in the facilitation of allogeneic SC engraftment without development of GVHD, a role for FC-CD3ε + cells in the induction of FoxP3 + CD4 + CD25 + regulatory T cells following allogeneic SC plus FC transplantation has been established.…”

“…To sort B220 + CD11b − CD11c + ppreDC: anti-CD45R/B220 (RA3-6B2) APC, anti-CD11b (M1/70) FITC and anti-CD11c (HL3) biotin, with streptavidin PE-Cy5 were used [5,20]. To sort spleen CD4 + CD25 − or CD4 + CD25 + cells: anti-CD4 (GK1.5) FITC and anti-CD25 (PC61) APC were used.…”

Spleen but not tumor infiltration by dendritic and T cells is increased by intravenous adenovirus-Flt3 ligand injection

“…The DC subset secretes cytokines that may have skewed T cells away from the type 1 phenotype and induced a tolerant phenotype. 29,30 Following Adv-Flt3L treatment, splenic B and NK cell numbers were also increased with kinetics similar to the DCs, whereas T-cell numbers continued to rise through at least day 22 following Adv-Flt3L injection. Thus, at a dose of 1 Â 10 11 VPs, i.v.…”

Immunosuppression for lung transplantation

“…Moreover, many anti-inflammatory or immunosuppressive drugs commonly used in transplantation, inhibit the maturation of DCs and potentiate their tolerogenicity (101). Plasmatoid DCs represent a recently characterized DC subset, the precursor of which can enhance allogeneic hematopoietic stem cell engraftment and promote donor-specific tolerance to skin grafts in mice (102). This ability to tolerize the indirect pathway may be particularly important for the prevention of chronic rejection.…”