| Dendritic cells (DC) are powerful antigen-presenting cells and can be used as vaccines to induce cell-mediated immunity. While knowledge of DC has grown rapidly in these past years, it has remained a challenge to understand how dendritic cells interact with T cells and how this regulates the development of immune responses. Results have implication for the preparation of effective vaccines, in particular for cancer immunotherapy. Our approach has been to produce and to study human dendritic cells in vitro and to measure the regulation of cytokine production in immune responses. We determined that environmental signals received by DC played a major role in the development of their functional properties. Among signals received by DC, the engagement of CD40 by CD40 ligand (CD40L) on T cells constitutes a pivotal event that induces maturation and cytokine secretion. In monocyte-derived DC, the effects of CD40L were modulated by co-factors such as IL-1β. In conjunction with CD40L, IL-1β upregulated IL-12 secretion by DC and had effects distinct from either IFN-γ or LPS, known modulators of IL-12. This provided a new mechanism linking an innate signal to the initiation of adaptive cellular immunity. The role of IL-1 family members in the regulation of other DC properties was further investigated. IL-1α or IL-1β, but not IL-18, acted with CD40L to induce a panel of inflammatory cytokine genes, including IL-12, the newly described IL-23, IL-10, IL-1β, IL-18 and IL-6. The constitutive expression of the IL-1 receptor antagonist prevented the induction of bioactive IL-12 by CD40L alone, providing evidence for the biological relevance of IL-1 in IL-12 production. Further, DC treated with CD40L and IL-1β surpassed CD40L-treated or immature DC for priming naïve T cells and inducing their differentiation. Analysis of the effect of cytokines, especially IL-1, and CD40L on DC has provided information about DC modulating the T cell stimulatory properties, and paved the way for the development of improved vaccines for tumor immunotherapy. |
