INTERLEUKIN-12 ACTS AS AN ADJUVANT FOR HUMORAL IMMUNITY THROUGH INTERFERON-GAMMA-DEPENDENT AND INTERFERON-GAMMA-INDEPENDENT MECHANISMS

Interleukin-12 (IL-12) is a pivotal cytokine that has dramatic effects on cell-mediated immunity. It is now becoming increasingly recognized that IL-12 also strongly controls humoral immunity. We have investiga ted the mechanism by which IL-12 induces alterations in antibody isoty pe expression by determining the influence of IL-12 on in vitro immuno globulin (Ig) production in polyclonally activated murine spleen cell cultures. Cells exposed to IL-12 plus lipopolysaccharide or anti-CD40 monoclonal antibody showed dramatically elevated IgG2a and suppressed IgG1 production compared to cells cultured in the absence of IL-12. IL -12 treatment of spleen cell cultures induced expression of gamma 2a g erm-line transcripts, consistent with initiation of switch recombinati on to IgG2a. In addition, exposure of limiting dilution cultures to IL -12 increased IgG2a(+) cell precursor frequency. All of the above resu lts were dependent on interferon-gamma (IFN-gamma). However, in the ab sence of IFN-gamma, IL-12 still had significant effects on Ig secretio n. Specifically, IL-12 enhanced IgG1 and IgG2b anti-DNP antibody level s in mice containing specific disruptions in the IFN-gamma gene. Our r esults suggest that IL-12 induces T helper type 1 and natural killer c ells to secrete large amounts of IFN-gamma which then causes B cells t o switch to IgG2a and IgG3 production, In addition, IL-12 has direct o r indirect effects on B cells that are independent of IFN-gamma. The I FN-gamma-independent effects may include enhancement of Ig expression by post-switched cells.