CHARACTERIZATION OF THE FUNCTIONS INDUCED BY INTERFERON-λ3 IN HUMAN PLASMACYTOID DENDRITIC CELLS

Type III interferon (IFN) family is composed by IFNλ1, IFNλ2, IFNλ3 and the recently discovered IFNλ4. IFNλs are antiviral cytokine whose main function is to counteract viral spreading and promptly initiate the antiviral response in an infected host. For several years, this important role was thought to be peculiar of the well-known type I IFN family, composed by IFNα and IFNβ. Instead, both type I and type III IFN families elicit similar responses in cells expressing their specific receptors, activate similar signaling pathways and induce hundreds of interferondependent antiviral mediators. In the last years, after the discovery of IFNλs, increasing numbers of studies have detected their presence in the context of several viral-mediated pathologies affecting mainly the anatomic barriers and mucosal tissues. As an example, IFNλ3 contributions in modulating the immune response during HCV infection in the liver has been reported and highlighted by several important studies, even though its ultimate role during HCV pathogenesis remains not completely understood. Plasmacytoid dendritic cells (pDCs) are one of the DC subsets that, among other functions, are highly specialized in the production of type I IFNs, thus promoting antiviral immune responses. In fact, pDCs rapidly and strongly respond to viral particles and nucleic acids via potent secretion of IFNα, and subsequently present the captured viral antigens to T cells initiating adaptive immune response. More recently, pDCs have been shown to produce also IFNλs upon treatment with different types of viruses, coculture with HCV-infected cells or synthetic ligands for TLR7 and TLR9. Moreover, among leukocytes, only pDCs, and less prominently B cells, have been shown to express IFNλR, but only pDCs have been unequivocally shown to respond to IFNλs in terms of altered CD80 and MHC-I expression, STAT1 phosphorylation activation and MX1 mRNA induction. In this study, I have extensively analyzed how human pDCs respond upon incubation with IFNλ3. My data not only confirm the pDC responsiveness to IFNλs, but also greatly extend previous observations already reported for IFNλ1. The purpose of my study has been to achieve a comprehensive and more complete characterization of pDC behavior in the presence of IFNλ3. This could give us some important information on pDC peculiar skills, paving the way for further analysis on IFNλ-pDC crosstalk under specific context.