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Murine and Human IL-7 Activate STAT5 and Induce Proliferation of Normal Human Pro-B Cells¹

Sonja E. Johnson^*, Nisha Shah^*, Angela Panoskaltsis-Mortari^*, and Tucker W. LeBien^2,*,

^* The Cancer Center, Department of Pediatrics, and Department of Laboratory Medicine/Pathology, University of Minnesota Medical School, Minneapolis, MN 55455

The role of IL-7 in lymphoid development and T cell homeostasis has been extensively documented. However, the role of IL-7 in human B cell development remains unclear. We used a xenogeneic human cord blood stem cell/murine stromal cell culture to study the development of CD19⁺ B-lineage cells expressing the IL-7R. CD34⁺ cord blood stem cells were cultured on the MS-5 murine stromal cell line supplemented with human G-CSF and stem cell factor. Following an initial expansion of myeloid/monocytoid cells within the initial 2 wk, CD19⁺/pre-BCR^– pro-B cells emerged, of which 25–50% expressed the IL-7R. FACS-purified CD19⁺/IL-7R⁺ cells were larger and, when replated on MS-5, underwent a dose-dependent proliferative response to exogenous human IL-7 (0.01–10.0 ng/ml). Furthermore, STAT5 phosphorylation was induced by the same concentrations of human IL-7. CD19⁺/IL-7R^– cells were smaller and did not proliferate on MS-5 after stimulation with IL-7. In a search for cytokines that promote human B cell development in the cord blood stem cell/MS-5 culture, we made the unexpected finding that murine IL-7 plays a role. Murine IL-7 was detected in MS-5 supernatants by ELISA, recombinant murine IL-7 induced STAT5 phosphorylation in CD19⁺/IL-7R⁺ pro-B cells and human B-lineage acute lymphoblastic leukemias, and neutralizing anti-murine IL-7 inhibited development of CD19⁺ cells in the cord blood stem cell/MS-5 culture. Our results support a model wherein IL-7 transduces a replicative signal to normal human B-lineage cells that is complemented by additional stromal cell-derived signals essential for normal human B cell development.

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