CXCL12–CXCR4 Axis Is Required for Contact-Mediated Human B Lymphoid and Plasmacytoid Dendritic Cell Differentiation but Not T Lymphoid Generation

Abstract

We investigated the involvement of CXCL12-CXCR4 interactions in human lymphohematopoiesis by coculture with telomerized human stromal cells. CXCR4 expression was low in CD34CD38CD45RACD10CD7CD19 immature hematopoietic stem/precursor cells (HSPCs) but higher in CD34CD38CD45RACD10CD7CD19 early lymphoid precursors and even higher in CD34CD38CD45RACD10CD7CD19 pro-B cells. Inhibition of the effect of stromal cell-produced CXCL12 by an anti-CXCR4-blocking Ab suppressed the generation of CD45RACD10CD7CD19 early T lymphoid precursors (ETPs) and CD45RACD10CD7CD19 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 CD45RACD10CD7CD19 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. CD14CD11cHLA-DRCD123CD303 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.

Transcriptomic profiling of bovine blood dendritic cells and monocytes following TLR stimulation

“…The only cell subset responding to CpG stimulation in addition to the other ligands was pDC with significant downregulation of CCR2 and CCR5 and strong upregulation of CCR7 . The chemokine receptor CXCR4 , reported to be essential for development of human pDC [39] and highly transcribed in unstimulated bovine pDC and cM, was found to be downregulated in these cells, especially with Gardiquimod stimulation. For cDC2, we did not observe conclusive changes in the transcription of chemokine receptors.…”

Differential mast cell phenotypes in benign versus cancer tissues and prostate cancer oncologic outcomes

“…We further found differential expression of inflammatory pathway‐related genes, such as CXCR4 , on tumor‐infiltrating mast cells. CXCR4 is a chemokine receptor for CXCL12 that is expressed by inflammatory cells including T cells, macrophages, and mast cells, and has been shown to play a role in mast cell recruitment [25,32,33]. The CXCL12–CXCR4 pathway in mast cells has been causally implicated in several cancers, including UV‐induced skin cancer, glioblastoma, and prostate cancer [34–36].…”

Differential Mast Cell Phenotypes in Benign versus Cancer Tissues and Prostate Cancer Oncologic Outcomes

“…CXCR4 is a chemokine receptor for CXCL12 that is expressed by inflammatory cells including T cells, macrophages, and mast cells, and has been shown to play a role in mast cell recruitment [32,39,40]. The CXCL12-CXCR4 pathway in mast cells has been causally implicated in several cancers, including UV induced skin cancer, glioblastoma, and prostate cancer [41][42][43].…”