Rj. Armitage et al., HUMAN B-CELL PROLIFERATION AND IG SECRETION INDUCED BY RECOMBINANT CD40 LIGAND ARE MODULATED BY SOLUBLE CYTOKINES, The Journal of immunology, 150(9), 1993, pp. 3671-3680
Recombinant human CD40 ligand (hCD40L) was expressed on the surface of
CV1/EBNA cells and examined for its ability to induce proliferation a
nd Ig secretion from human B cells in the presence or absence of solub
le cytokines. hCD40L was directly mitogenic in a dose-dependent fashio
n for purified tonsil B cells with maximal proliferation occurring at
days 5 to 7. Proliferation induced by CD40L was significantly enhanced
in the presence of IL-2, IL-4, or IL-10 and strongly suppressed by tr
ansforming growth factor-beta. Although IL-5, TNF-alpha, and IFN-gamma
had no stimulatory effect in the presence of hCD40L alone, if IL-4 wa
s also present in cultures, these cytokines enhanced the proliferative
response above that seen with IL-4 alone. Interestingly, in the absen
ce of IL-4, IFNgamma had an inhibitory effecton hCD40L-induced prolife
ration. Although CD40L alone did not enhance Ig secretion, addition of
IL-2 or IL-10 to the cultures significantly elevated the levels of Ig
M, IgG1, and IgA that were observed. Addition of IL-4 to the cultures
did not enhance secretion of these isotypes but had a weak inhibitory
effect. However, CD40L-mediated induction of IgG4 and IgE was dependen
t on the presence of IL-4. Of the cytokines examined, only IL-10 enhan
ced IgE secretion under these conditions. Although transforming growth
factor-beta only partially inhibited secretion of IgM, IgG1, and IgA,
it was strongly suppressive for IgG4 and IgE production. Our data dem
onstrate that proliferation and Ig secretion induced in the presence o
f CD40L can be modulated in a positive and negative fashion by soluble
cytokines. IL-2 and IL-10 specifically enhance IgM, IgG1, and IgA pro
duction although IL-4, despite costimulating B cell proliferation, doe
s not augment secretion of these isotypes but provided an essential co
signal with CD40L for the production of IgG4 and IgE.