DOCK2 Is Critical for CD8+TCR− Graft Facilitating Cells to Enhance Engraftment of Hematopoietic Stem and Progenitor Cells

Abstract

CD8 1 TCR 2 graft facilitating cells (FCs) enhance engraftment of hematopoietic stem cells (HSCs) in allogeneic and syngeneic recipients. The mechanisms by which FCs promote HSC engraftment and tolerance induction have not been fully elucidated. Here, we provide data to support a critical role for dedicator of cytokinesis 2 (DOCK2) in multiple aspects of FCs function. DOCK2 2/2 FCs exhibit compromised facilitative function in vivo as evidenced by the loss of engraftmentenhancing capability for c-Kit 1 Sca-1 1 lineage 2 (KSL) cells, and compromised ability to promote KSL cell homing and lodgment in hematopoietic niche. Deletion of DOCK2 abrogates the ability of FCs to induce differentiation of na€ ıve CD4 1 CD25 2 T cells into FoxP3 1 regulatory T cells and interleukin-10-producing type 1 regulatory T cells in vitro. Moreover, DOCK2 2/2 FCs are unable to promote survival of KSL cells when cocultured with KSL cells. DOCK2 2/2 FCs also exhibit compromised migration to stroma-derived factor-1 in vitro and impaired homing to the bone marrow in vivo. In conclusion, our results demonstrate that DOCK2 is critical for FCs to maintain its immunomodulatory function and exert its trophic effects on KSL cells. These findings may have direct clinical relevance to promote HSC engraftment for treatment of autoimmunity, hemoglobinopathies, and to induce transplantation tolerance.

RETRACTED: Characterization of Human CD8+TCR− Facilitating Cells In Vitro and In Vivo in a NOD/SCID/IL2rγnull Mouse Model

“…The majority of mouse FC resemble tolerogenic plasmacytoid precursor (p-pre) dendritic cells (DC) phenotypically and functionally in cytokine production. FC potently suppress GVHD by generating CD4 + /CD25 + /FoxP3 + regulatory T cells (T reg ) 6, 7 as well as interleukin (IL)-10-producing Type 1 regulatory T cells 8 . Our recent studies show that FC induce antigen-specific T reg in vivo 6 .…”

Dock2 in the development of inflammation and cancer

“…During HSCT, CD8 + TCR − graft facilitating cells (FCs) enhance engraftment of HSC into recipients. A study with Dock2 −/− FCs decreased the survival of c-Kit + Sca-1 + lineage − (KSL) cells and their homing and lodgment into the hematopoietic niche [53]. In addition, the ability of FCs to induce differentiation of naive CD4 + CD25 − T cells into FoxP3 + regulatory T cells and interleukin-10-producing type 1 regulatory T cells was reduced significantly in Dock2 −/− mice in comparison with controls [53].…”

Facilitating cells in tolerance induction for kidney transplantation

“…The facilitating cell population is a tolerogenic cell population that has been shown to induce a number of immunomodulatory effects, including CD4 þ /CD25 þ / FoxP3 þ antigen-specific T regs in vivo and in vitro as well as to induce interleukin-10-producing Trl cells, both recognized as important components in the establishment of immunological tolerance [45][46][47].…”