Interferon-[alpha] Abrogates Tolerance Induction by Human Tolerogenic Dendritic Cells

Administration of interferon-[alpha] (IFN-[alpha]) represents an approved adjuvant therapy as reported for malignancies like melanoma and several viral infections. In malignant diseases, tolerance processes are critically involved in tumor progression. In this study, the effect of IFN-[alpha] on tolerance induction by human tolerogenic dendritic cells (DC) was analyzed. We focussed on tolerogenic IL-10-modulated DC (IL-10 DC) that are known to induce anergic regulatory T cells (iTregs). IFN-[alpha] promoted an enhanced maturation of IL-10 DC as demonstrated by upregulation of the differentiation marker CD83 as well as costimulatory molecules. IFN-[alpha] treatment resulted in an increased capacity of DC to stimulate T cell activation compared to control tolerogenic DC. We observed a strengthened T cell proliferation and increased IFN-[gamma] production of CD4.sup.+ and CD8.sup.+ T cells stimulated by IFN-[alpha]-DC, demonstrating a restoration of the immunogenic capacity of tolerogenic DC in the presence of IFN-[alpha]. Notably, restimulation experiments revealed that IFN-[alpha] treatment of tolerogenic DC abolished the induction of T cell anergy and suppressor function of iTregs. In contrast, IFN-[alpha] neither affected the priming of iTregs nor converted iTregs into effector T cells. IFN-[alpha] inhibits the induction of T cell tolerance by reversing the tolerogenic function of human DC.