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Blood, 1 May 2001, Vol. 97, No. 9, pp. 2708-2715

IMMUNOBIOLOGY

Characteristics of early murine B-lymphocyte precursors and their direct sensitivity to negative regulators

Taku Kouro, Kay L. Medina, Kenji Oritani, and Paul W. Kincade

From the Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; and the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Japan.

Recently, a collection of surface markers was exploited to isolate viable Lin- TdT+ cells from murine bone marrow. These early pro-B cells were enriched for B-lineage lymphocyte precursor activity measured by short-term culture and had little responsiveness to myeloid growth factors. Early precursors can be propagated with remarkably high cloning frequencies in stromal cell-free, serum-free cultures, permitting this analysis of direct regulatory factors. Expression of the interleukin-7 receptor (IL-7Ralpha ) chain marks functional precursors and IL-7 is necessary for progression beyond the CD45RA+ CD19- stage. Efficient survival and differentiation were only observed when stem cell factor and Flt-3 ligand were also present. IL-7-responsive CD19+ precursors are estrogen resistant. However, B-lineage differentiation was selectively abrogated when highly purified Lin- precursors were treated with hormone in the absence of stromal cells. In addition, early stages of B lymphopoiesis were arrested by limitin, a new interferon (IFN)-like cytokine as well as IFN-alpha , IFN-gamma , or transforming growth factor beta  (TGF-beta ), but not by epidermal growth factor (EGF). Lin- TdT+ early pro-B cells are shown here to be CD27+ AA4.1+/-Ki-67+ Ly-6C- Ly-6A/Sca-1Lo/-Thy-1-CD43+ CD4+/-CD16/32Lo/-CD44Hi and similar in some respects to the "common lymphoid progenitors" (CLP) identified by others. Although early pro-B cells have lost myeloid differentiation potential, transplantation experiments described here reveal that at least some can generate T lymphocytes. Of particular importance is the demonstration that a pivotal early stage of lymphopoiesis is directly sensitive to negative regulation by hormones and cytokines.

© 2001 by The American Society of Hematology.
 

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