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

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.