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Human pre-B cells differentiate into Ig-secreting plasma cells in the
presence of interleukin-4 and activated CD4+ T cells or their membranes
J Punnonen, G Aversa and JE de Vries
DNAX Research Institute of Molecular and Cellular Biology, Human Immunology
Department, Palo Alto, CA 94304-1104.
Studies on human B-cell development have been hampered by the lack of
reproducible culture techniques to induce pre-B cells to differentiate into
Ig-secreting plasma cells. Here, we describe that highly purified surface
(s) mu-, cytoplasmic (c) mu+, CD10+, CD19+ human pre-B cells derived from
fetal bone marrow (BM) differentiate with high frequencies into
Ig-secreting plasma cells, when cocultured with activated, cloned CD4+ T
cells and with interleukin-4 (IL-4). Production of IgM, total IgG, IgG4,
and IgE in pre-B-cell cultures was detected, indicating that the cells also
underwent Ig isotype switching. Pre-B-cell differentiation occurred in the
absence of BM stromal cells, IL-7, and stem cell factor (SCF). However,
IL-7 significantly enhanced the levels of Ig produced, whereas SCF was
ineffective. Neutralizing anti-IL-4 monoclonal antibodies (MoAbs)
completely inhibited pre-B-cell differentiation showing the specificity of
the reaction. Intact CD4+ T- cell clones could be replaced by membrane
preparations of these cells, indicating that the costimulatory signals
provided by the activated CD4+ T cells are contact-mediated. In contrast,
anti-CD40 MoAbs failed to provide the costimulatory signal required for
pre-B-cell differentiation, which may be related to the very low expression
of CD40 on fetal BM B cells. Activated CD4+ T cells and IL-4 also induced s
mu expression and Ig synthesis in cultures initiated with pre-B cells that
had been preincubated in medium for 2 days, and from which spontaneously
emerging s mu+ B cells were removed by using a fluorescence-activated cell
sorter. These results support the notion that the Ig synthesis observed in
pre-B-cell cultures was not caused by outgrowth and differentiation of
cells that spontaneously matured into s mu+ B cells. In addition, IL-4 and
CD4+ T cells strongly enhanced CD40 and HLA-DR expression on the majority
of cultured pre-B cells, further indicating that CD4+ T cells and IL-4
activate bona fide pre-B cells. Taken together, these data indicate that
activated CD4+ T cells and IL-4 can provide all the necessary signals
required for human pre-B cells to differentiate into Ig-secreting plasma
cells.
Volume 82,
Issue 9,
pp. 2781-2789,
11/01/1993
Copyright © 1993 by The American Society of Hematology
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