Fms-Like Tyrosine Kinase 3-Ligand Contributes to the Development and Function of the Subpopulation of CD8α⁺ Plasmacytoid Precursor Dendritic Cells in CD8⁺ /TCR^- Facilitating Cells.

Abstract

Facilitating cells (FC) are a CD8⁺ TCR^- bone marrow subpopulation that enhance engraftment of purified hematopoietic stem cells (HSC) and induce antigen-specific CD4⁺ CD25⁺ FoxP3⁺ regulatory T cell (Treg) in vivo. The major subpopulation in FC resembles plasmacytoid precursor dendritic cells (p-preDC) both phenotypically and functionally. Here, we report that the number of FC was significantly reduced in Fms-like tyrosine kinase 3-ligand-knockout (Flt3-L-KO) mice. Specifically, there was a selective decrease in the B220⁺ CD11c⁺ CD11b^- p-preDC FC subpopulation. The p-preDC FC subpopulation in FC total is restored after Flt3-L administration to Flt3-L-KO mice. FC from Flt3-L-KO donors exhibit impaired facilitation of allogeneic HSC engraftment in ablatively conditioned mice (B6 → NOD) as well as in mice conditioned with reduced intensity conditioning (B6 → BALB/c). In addition, the number of CD4⁺ CD25⁺ Foxp3⁺ Treg from Flt3-L-KO mice is significantly decreased. This was associated with the expression of chemokine receptor CXCR3⁺ or CCR5⁺ on Treg. Treg from the spleen of Flt3-L-KO mice showed impaired facilitation of engraftment of allogeneic HSC compared to wild-type Treg. Flt3-L treatment significantly expanded Treg, and restored their facilitating function. These results suggest that Flt3-L is an important growth factor in the development and homeostasis of p-preDC FC and in the role of FC inducing generation of Treg. Flt3-L provides potent immunoregulatory properties that may be clinically useful to improve tolerance induction and enhance the function of allogeneic cell therapies. Stem Cells 2018;36:1567-1577.