IL-10-producing dendritic cell biology and their applications to control unwanted immune responses

The induction and maintenance of tolerance is a mechanism controlled by both the innate and adaptive branches of the immune system. The myeloid actors in the induction of peripheral tolerance are dendritic cells (DC), either at immature stage or specialized subsets, called tolerogenic DC (tolDC). TolDC control effector T cells and promote T regulatory cells (Tregs), which suppress immune system activation and avoid detrimental self-reactivity, preventing autoimmunity.
We focused our research on IL-10-secreting DC recently identified as the best-suited cells for DC-based therapies. We identify and characterized a subset of IL-10-prpducign DC, termed DC-10 as key player in the induction of IL-10-mediated tolerance and in the induction of T regulatory type 1 (Tr1) cells. The discovery that DC-10 are present in vivo, can modulate T-cell responses, induce Tr1 cells in vitro, and are associated with tolerance prompted us to postulate that DC-10 represent an important subset of naturally-occurring DC involved in tolerance in autoimmune disease. Thanks to the precise monitoring of DC-10 in the peripheral blood we demonstrated that low frequency and function of DC-10 is associated with autoimmune patients and inflammation. These results prompted the generation of IL-10-producing DC by lentiviral vector gene transfer for cell-based approaches to restore IL-10-mediated tolerance. We showed that engineered IL-10 DC are effective in modulating T cell responses and promoting antigen-specific Tr1 cells in vitro and in vivo. Our study will provide new insights into the tolerogenic role of DC-10 and will open new perspectives for IL- 10-producing DC cell therapy to re-establish tolerance in autoimmune diseases.

Dr. Silvia Gregori graduated in Biological Sciences at the University of Milan, where she later specialized in Biotechnology. After an experience in London, she returned to Italy to work in the research laboratories of Roche Milano Ricerche, where she dissected the role of Vitamin D3 and its analogues in modulating T cell responses in autoimmunity and performed seminal works on the role of regulatory T cells in autoimmune diabetes. Since 2001, she has been working at San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), where she elucidated new mechanisms of suppression mediated by T regulatory type 1 (Tr1) cells and identified DC-10 as major subset of dendritic cells involved in Tr1 cell differentiation. Dr. Gregori is currently a Group Leader and led the “Meccanisms of Peripheral Tolerance” Unit at SR-Tiget. Her research focuses on IL-10-secreting DC. Her basic studies focused on IL-10 regulatory cells and in particular to DC-10, and their role in promoting/maintaining IL-10-mediated tolerance in healthy and pathological conditions. Her translational studies aim at developing innovative DC-based approaches, by means of exogenous IL-10 and/or lentiviral vector (LV)-mediated gene transfer, for the modulation of T-cell mediated diseases.