Novel Lymphoid Pathway of Human Plasmacytoid and Conventional Dendritic Cells

[Introduction]

Dendritic cells (DCs) play a central role in initiation and regulation of immune response. Human plasmacytoid DCs (pDCs) as well as conventional DCs (cDCs) were shown to differentiate from multi-lymphoid progenitors (MLPs) as well as myeloid progenitors via common DC progenitors. However, lymphoid pathway of DCs remained clarified. Here we investigated lymphoid origin of DCs, using a novel co-culture system which supports differentiation of various lineages of lymphoid and DCs (Br J Haematol. 157:674, 2012; J Immunol. 199:2343, 2017).

[Methods and Results]

CD34⁺CD38^-CD45RA^-CD10^-CD7^- human hematopoietic stem/progenitor cells (HSPCs) and various lymphoid progenitors including CD34⁺CD38^-CD45RA⁺CD10^-CD7^-lymphoid-primed multipotent progenitors (LMPPs), CD34⁺CD38^-CD45RA⁺CD10⁺ MLPs,and CD34⁺CD38⁺CD45RA⁺CD10⁺CD7^-CD19^- (10SPs), generally though as B/NK progenitors, were isolated from cord blood and cocultured with telomerized human stromal cells with SCF, flt3L, TPO, and GM-CSF. After 17 to 21 days, generation of CD45RA⁺CD19⁺ proB, CD56⁺CD3^- NK cells, HLA-DR⁺IL-3R^highCD303⁺CD304⁺pDCs, and CD1c⁺cDCs was assessed. We observed that not only immature HSPCs, LMPPs and MLPs but also 10SPs gave rise to pDC and cDCs in addition to proB, NK cells. 10SPs were found to be subdivided by expression pattern of c-kit and IL-7 receptor (R), and similarly cocultured with stromal cells. pDCs, cDCs, proB, and NK cells were generated from c-kit⁺IL-7R^- fraction, while pDC, cDCs, and proB, but few or no NK cells were generated from c-kit⁺IL-7R⁺ fractions. c-kit^-IL-7R⁺ fraction produced a significantly lower number of cells than c-kit⁺IL-7R^+or- fractions and mainly differentiated into proB cells. By single cell assay of 10SPs, progenitors with differentiation potential for pDC, cDC, and/or proB were detected. These data revealed a differentiation pathway of pDCs and cDCs from relatively mature lymphoid progenitors and suggested the presence of DC and B common progenitors.

[Summary]

The present study uncovered a closed relationship between B-lymphoid and DC differentiation pathway. We are further attempting to delineate their relationship and differentiation process toward pDCs, cDCs, and proB.