Human non-germinal center B cell interleukin (IL)-12 production is primarily regulated by T cell signals CD40 ligand, interferon gamma, and IL-10: Role of B cells in the maintenance of T cell responses
Jl. Schultze et al., Human non-germinal center B cell interleukin (IL)-12 production is primarily regulated by T cell signals CD40 ligand, interferon gamma, and IL-10: Role of B cells in the maintenance of T cell responses, J EXP MED, 189(1), 1999, pp. 1-11
Interleukin (IL)-12 is expressed mainly in antigen-presenting cells after c
hallenge with microbial material or after CD-40 activation. Although IL-12
was cloned from human Epstein-Barr virus (EBV)-transformed B cell lines, su
rprisingly, CD-IO ligation on murine B cells did not lead to IL-12 producti
on, suggesting that murine B cells do not produce IL-12. Here we demonstrat
e that a subset of human tonsillar B cells can be induced to er;press and s
ecrete bioactive IL-12. The major stimulus to produce IL-12 in human B cell
s was CD40 ligation. In contrast, B cell receptor cross-linking did not ind
uce IL-12. Expression of IL-12 after CD-CO activation was restricted to CD3
8(-) IgD(+) non-germinal center (non-GC) B cells. CD40 ligation and interfe
ron (IFN)-gamma exhibited synergistic effects on IL-12 production, whereas
IL-10 abrogated and IL-4 significantly inhibited IL-12 production by these
B cells. In contrast to IL-12 of IL-6 is conversely regulated, leading to s
ignificant increase after CD40 Ligation in dir presence of the T helper typ
e 2 (Th2) cytokine IL-3. Cord blood T cells skewed towards either a Th1 or
a Th2 phenotype maintained their cytokine expression pattern when restimula
ted with allogeneic resting B cells. Blockade of CD40 and/or IL-12. during
T-B interaction significantly reduced IFN-gamma production by the T cells.
This suggests a model whereby B cells produce either IL-12 or IL-G after co
ntact with I cells previously differentiated towards Th1 or Th2. Furthermor
e, IL-12 and IL-6 might provide a positive feedback during cognate T-B inte
ractions, thereby maintaining T cells' differentiation pattern during ampli
fication of the immune response.