Accessory signaling by CD40 for T cell activation: Induction of Th1 and Th2 cytokines and synergy with interleukin-12 for interferon-gamma production

The interaction of CD40 ligand (CD40L) on activated T cells with CD40 on B cells, monocytes and dendritic cells is essential for humoral immunity and for up-regulation of antigen-presenting cell (APC) functions, as a result of signaling through CD40. There are also some indications that after interaction with CD40, CD40L can directly signal T cells. In this study we demonstrate that upon stimulation of human peripheral blood T cells through the T cell receptor (TCR)/CD3 complex, CD40/CD40L interaction strongly enhances the production of Th1 cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma and Th2 cytokines such as IL-4, IL-5 and IL-10 by a direct effect on T cells. Furthermore, CD40/CD40L interaction synergizes with IL-12 in selectively enhancing IFN-gamma production by purified anti-CD3-stimulated T cells. These effects were observed at both the protein and the mRNA level. Both CD4(+) and CD8(+) T cells were able to produce IFN-gamma in the presence of helper signals from IL-12 and CD40, although CD8(+) T cells were less active. Since CD40/CD40L interaction also upregulates IL-12 production and B7 expression by APC, our results suggest that CD40/CD40L interaction is bidirectional, and promotes activation of both APC and T cells.