NORMAL B-CELLS FAIL TO SECRETE INTERLEUKIN-12

Interleukin-12 is a key regulatory cytokine produced by antigen-presen ting cells (APC) which drives the development of interferon-gamma (IFN -gamma)-producing cells and promotes cell-mediated immunity. Following subcutaneous immunization with protein antigen in adjuvant, dendritic cells (DC) but not small nor large B cells in immune lymph nodes expr ess antigenic complexes and secrete substantial amounts of bioactive I L-12 p75 upon antigen-specific interaction with T cells. We have analy zed secretion of IL-12 p40 and p75 by cell populations enriched in DC, macrophages or B cells in response to nonspecific stimulation or to i nteraction with antigen-specific CD4(+) cells. These APC populations d o not produce IL-12 constitutively but, upon stimulation with heat-fix ed Staphylococcus aureus and IFN-gamma, IL-12 p40 and p75 are secreted by DC and macrophages, whereas B cells fail to produce IL-12. B cells also fail to secrete IL-12 in response to stimulation with LPS and IF N-gamma. Co-culture with CD4(+) Thybridoma cells and antigen induces I L-12 secretion by DC. Up-regulation of IL-12 secretion by interaction with antigen-specific CD4(+) T cells is abrogated by anti-class II mon oclonal antibodies (mAb), by soluble CD40 molecules and by anti-CD40 l igand mAb, demonstrating a positive feedback between T cells and DC me diated by TCR-peptide/class II and by CD40-CD40 ligand interactions. E xpression of class II and CD40 molecules is comparable in B cells and DC, and both APC types activate CD4(+) T cells. Yet, even upon interac tion with antigen-specific T cells, B cells fail to secrete IL-12. The capacity of B cells to present antigen but not to secrete IL-12 may e xplain their propensity to selectively drive T helper type 2 cell deve lopment.