Expression of Interleukin-7 Receptor by Lineage-Negative Human Bone Marrow Progenitors With Enhanced Lymphoid Proliferative Potential and B-Lineage Differentiation Capacity

Abstract

Relatively little is known about the relationship of lymphoid-associated gene expression to the proliferation and differentiation potential of early human bone marrow lymphoid progenitors. Surface expression of interleukin-7 (IL-7) receptor-α (IL-7Rα), a component of the high-affinity receptor for the lymphoid precursor growth factor IL-7, defined a CD34+ progenitor subset lacking the CD19+ pro-B phenotype but demonstrating markedly enhanced lymphoid clonogenic capacity and the ability to differentiate into pro-B cells in short-term culture. These progenitors expressed mRNA for the lymphoid-associated genes Igβ, RAG-1, and PAX-5, and were uniformly TdT-positive (TdT+). In contrast, IL-7Rα−/CD19−/CD34+ progenitors had a 50-fold reduced lymphoid clonogenic capacity and did not differentiate into pro-B cells in short-term culture. Expression of TdT and the lymphoid-associated genes Igβ and RAG-1, but not PAX-5, was detected in this fraction, although at lower levels than in the IL-7Rα+ progenitors. In contrast to IL-7Rα, loss of the stem cell factor receptor c-kit was associated with enhanced lymphoid clonogenic potential and increased B-lineage differentiation potential. These results indicate that IL-7Rα expression defines entry into a developmental stage characterized by upregulation of multiple lymphoid-associated genes and enhanced fitness for B-lymphoid differentiation. The onset of IL-7Rα and PAX-5 expression immediately before acquisition of CD19 is consistent with evidence suggesting upregulation of CD19 through pathways involving PAX-5 and IL-7.

Early B-lymphocyte precursors and their regulation by sex steroids

“…There are also some notable differences in characteristics of cells that express the enzyme. For example, the TdT + cells in humans are CD34 + and few are c-kit + (43). This is in contrast to the mouse where the majority of TdT + cells are c-kit lo and CD34 -.…”

“…CD45RA appears prior to CD19 in mouse and man. However, most human TdT + cells are CD45RA + while a majority of murine TdT + precursors are CD45RA - (8,10,43).…”

Common cytokine receptor γ chain (γc)-deficient B cells persist in T cell-deficient γc mice and respond to a T-independent antigen

“…Does the incomplete reconstitution of peripheral B cell numbers in the double-mutant mice reflect species-specific differences in the IL-7 dependence of the B cell development? While some data support an important role for IL-7 during human B cell develoment [24][25][26], others demonstrate that IL-7independent B cell development can occur in man [27]. The fact that SCIDX1 patients have normal numbers of B cells supports the latter finding, but whether IL-7independent B cell development in man is a major or minor developmental pathway under normal conditions remains to be determined.…”

A combination of stem cell factor and granulocyte colony-stimulating factor enhances the growth of human progenitor B cells supported by murine stromal cell line MS-5

“…Recently, Ryan et al [22] reported that progenitor B cells did not express c-Kit. We also detected G-CSFR, but not c-Kit, on the progenitor B cells by flow cytometry.…”