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Human Non-Germinal Center B Cell Interleukin (IL)-12 Production Is Primarily Regulated by T Cell Signals CD40 Ligand, Interferon , and IL-10: Role of B Cells in the Maintenance of T Cell Responses

From the Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Interleukin (IL)-12 is expressed mainly in antigen-presenting cells after challenge with microbial material or after CD40 activation. Although IL-12 was cloned from human Epstein-Barr virus (EBV)-transformed B cell lines, surprisingly, CD40 ligation on murine B cells did not lead to IL-12 production, suggesting that murine B cells do not produce IL-12. Here we demonstrate that a subset of human tonsillar B cells can be induced to express and secrete bioactive IL-12. The major stimulus to produce IL-12 in human B cells was CD40 ligation. In contrast, B cell receptor cross-linking did not induce IL-12. Expression of IL-12 after CD40 activation was restricted to CD38^–IgD^± non-germinal center (non-GC) B cells. CD40 ligation and interferon (IFN)- 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, production of IL-6 is conversely regulated, leading to significant increase after CD40 ligation in the presence of the T helper type 2 (Th2) cytokine IL-4. Cord blood T cells skewed towards either a Th1 or a Th2 phenotype maintained their cytokine expression pattern when restimulated with allogeneic resting B cells. Blockade of CD40 and/or IL-12 during T–B interaction significantly reduced IFN- production by the T cells. This suggests a model whereby B cells produce either IL-12 or IL-6 after contact with T cells previously differentiated towards Th1 or Th2. Furthermore, IL-12 and IL-6 might provide a positive feedback during cognate T–B interactions, thereby maintaining T cells' differentiation pattern during amplification of the immune response.

Key Words: interleukin 12 • B lymphocytes • CD40 • interferon • interleukin 10

J.L. Schultze was a Fellow of the Lymphoma Research Foundation of America when most of the work was performed and is currently a Special Fellow of the Leukemia Society of America. This work was supported by National Institutes of Health grant CA66996 to L.M. Nadler.

Abbreviations used: DC, dendritic cell; GC, germinal center; MBD, magnetic bead depletion; MIF, mean intensity of fluorescence; rh, recombinant human; sIg, surface immunoglobulin; t-CD40L, CD40 ligand transfectants; t-mock, control transfectants.

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