Underproduction of interleukin-12 in susceptible mice during progressive leishmaniasis is due to decreased CD40 activity.

Interleukin-12 promotes Th1 lymphocyte responses necessary for the cure of murine Leishmania major infection. We found that IL-12 p40 mRNA expression peaked at 4 weeks of infection in resistant C57BL/6 mice at levels threefold greater than in BALB/c mice. Peak IL-12 p40 expression in both strains was reduced threefold following treatment with neutralizing anti-CD40 ligand antibody and disease worsened in C57BL/6 mice. Direct activation of cultured lymph node cells by anti-CD40 MAb or soluble CD40 ligand failed to restore deficient IL-12 production by infected BALB/c mice unless recombinant IFN-beta was added to culture. Infected BALB/c lymph nodes also contained two- to threefold fewer low-density CD40+ accessory cells compared to that in C57BL/6 mice. We conclude that CD40-dependent responses are continually required for healing of leishmaniasis and that progressive disease is associated with decreased CD40-stimulated IL-12 synthesis as a consequence of either altered cytokine environment or inadequate accessory cell number.