Ph.D. Projects


Biological and molecular characterization of DC-10, a novel subset of human tolerogenic dendritic cells.
Supervisor: Silvia Gregori
Host Institute: HSR-TIGET

Dendritic cells (DC) are specialized antigen-presenting cells that play a critical role in initiating T-cell responses and in inducing both immunity and tolerance. DC in a steady state or a specialized subset of DC, termed tolerogenic DC, are critically involved in promoting and maintaining tolerance via the induction of adaptive type 1 regulatory T (Tr1) cells. We identify a subset of human DC, termed DC-10, which are present in vivo and can be induced in vitro in the presence of IL-10. DC-10 are characterized by the expression of tolerogenic molecules such as immunoglobulin-like transcript (ILT)4, and HLA-G antigen, secrete high levels of IL-10 but not IL-12, and efficiently induce anergic T cells that contain a significant proportion of already differentiated Tr1 cells. Anergized T cells suppress naïve CD4+ T cells stimulated with mature DC in vitro, consistent with the presence of functionally differentiated Tr1 cells in the culture.

The aim of this project is to improve our understanding in the biology of DC-10 and to further determine their impact in the modulation of the immune responses. To this aim, we will further investigate the molecular mechanisms by which DC-10 either differentiated in vitro from peripheral blood monocyte or isolated ex-vivo promote Tr1 cell differentiation. We will elucidate whether the unique tolerogenic function of DC-10 is dependent on autocrine production of IL-10. To this end endogenous IL-10 will be knock down in in vitro differentiated or in ex vivo isolated DC-10 using different strategies inclusing lentiviral vectors encoding for shRNA specific for IL-10, oligos against IL-10, or plasmid containing siRNA anti-IL-10. Phenotype, cytokine production profile, and biological functions of resulting DC will be estensively investigated. Moreover, we will determine the tolerogenic signature of DC-10 using microarray analyses with the final goal to identify a specific biomarker for DC-10.

Results will be instrumental not only to improve our knowledge on the role of DC-10 in promoting tolerance via adaptive Tr1 cells, but also to develop new tools aimed at modulating T-cell mediated disease through induction of Tr1 cells.