We investigated the involvement of CXCL12-CXCR4 interactions in human lymphohematopoiesis by coculture with telomerized human stromal cells. CXCR4 expression was low in CD34⁺CD38^-CD45RA^-CD10^-CD7^-CD19^- immature hematopoietic stem/precursor cells (HSPCs) but higher in CD34⁺CD38^-CD45RA⁺CD10⁺CD7^+/-CD19^- early lymphoid precursors and even higher in CD34⁺CD38⁺CD45RA⁺CD10⁺CD7^-CD19⁺ pro-B cells. Inhibition of the effect of stromal cell-produced CXCL12 by an anti-CXCR4-blocking Ab suppressed the generation of CD45RA⁺CD10^-CD7⁺CD19^- early T lymphoid precursors (ETPs) and CD45RA⁺CD10⁺CD7^-CD19^+/- B lymphoid precursors on stromal cells, but it did not affect the generation of ETPs in conditioned medium of stromal cell cultures. Replating assays showed that contact with stromal cells was critical for HSPC-derived CD45RA⁺CD10⁺CD7^-CD19^- B lineage-biased precursors to differentiate into CD19⁺ pro-B cells, which was suppressed by the anti-CXCR4 Ab. Conversely, HSPC-derived ETPs possessed T and B lymphoid and monocytic differentiation potential; stromal cell contact was not required for their growth but rather promoted B lymphoid differentiation. The anti-CXCR4 Ab did not affect the growth of ETPs in conditioned medium, but it suppressed their B lymphoid differentiation on stromal cells. CD14^-CD11c^-HLA-DR⁺CD123^highCD303⁺ plasmacytoid dendritic cells developed from HSPCs and ETPs exclusively in contact with stromal cells, which was suppressed by the anti-CXCR4 Ab. These data indicate that CXCL12 plays an essential role in stromal cell contact-mediated B lymphoid and plasmacytoid dendritic cell differentiation from immature hematopoietic and early T lymphoid precursors with a multilineage differentiation potential, but it does not participate in contact-independent generation of early T lymphoid precursors.

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