Differential production of IL-12 in BALB/c and DBA/2 mice controls IL-4 versus IFN-gamma synthesis in primed CD4 lymphocytes.

The profile of cytokines produced by CD4 T cells is profoundly influenced by the presence of IL-12. Here we demonstrate that during re-stimulation of antigen-specific immune responses in vitro, antigen-primed lymph node cells from DBA/2 mice produced 3- to 30-fold more IL-12 than did cells from BALB/c mice, which are identical at the major histocompatibility locus. The strain differences in IL-12 production were observed only in antigen-driven responses (and not in responses induced by bacterial products), and were dependent upon an interaction between CD4 T cells and lymph node adherent cells. In addition, differences in the quantity of IL-12 produced by DBA/2 and BALB/c antigen-presenting cells (APC) was not dependent on differential production of IFN-gamma by T cells, since APC from DBA/2 mice still produced much greater quantities of IL-12 than did BALB/c APC when each was cultured with the same H-2d-restricted Th2 clones, in the complete absence of IFN-gamma, or when each was cultured with primed (BALB/c x DBA/2)F1 T cells. The level of IL-12 produced in the cultures critically affected cytokine production in CD4 T cells, since neutralization of endogenous IL-12 in DBA/2 cultures, which are predisposed towards developing Th1 responses, reduced IFN-gamma production and enhanced IL-4 synthesis to levels normally seen in BALB/c cultures, which are predisposed toward developing Th2 responses. We propose therefore that differential production of antigen-driven IL-12 is a mechanism by which the genetic background in DBA/2 and BALB/c mice can affect the pattern of cytokine synthesis by T cells during the development of adaptive immune responses.