EMBRACING slanDC · Exploring the Molecular Bases that Regulate Apoptosis, Cytokine production and Interaction with Neutrophil Granulocytes by 6-sulfo LacNAc+ dendritic cells (slanDC)

Dendritic cells (DC) are composed of multiple subsets with distinct functions at the interface of the innate and adaptive immunity. Two major subsets of DC circulate in human peripheral blood: the myeloid DC (mDC) and the plasmacytoid DC (pDC), which can be distinguished by the expression of specific surface markers. Within mDC, slanDC are the most abundant in human blood and are characterized by a selective phenotype (6-sulfo LacNAc+, CD1c–, CD11c+, CD14–, CD16+, CD45RA+, C5aR+). They undergo spontaneous maturation if cultured in the absence of erythrocytes. Once matured, they are characterized by a high potential to produce pro-inflammatory cytokines such as IL-12p70 and TNFα, to prime naive T cells to become Th1 cells and to activate NK cell responses. While slanDCs may certainly play a crucial role in the control of immune response, a detailed knowledge on their involvement in autoimmunity, transplantation rejection and cancer biology is still missing. The central importance of slanDC in immune regulation makes, therefore, additional studies necessary to better understand the biologic role of this DC subset. For such a purpose, the project will focus on three main objectives:(1) to study the molecular mechanism(s) regulating IL-12p70 production by slanDC during their maturation and their cross-talk with neutrophils. To reach this objective, I will determine how IL-12p70 gene expression is controlled at a transcriptional and post-transcriptional level upon activation by TLR agonists and other stimuli.(2) to investigate the molecular mechanism(s) whereby LPS regulates slanDC survival: expression of Bcl-2 family proteins and ceramide metabolism will be analyzed.(3) to study the pattern of chemokine/chemokine receptor expression by TLR-activated slanDC.Results obtained from this project will provide new knowledge on the functional specializations of human DC subsets and, therefore, new concepts to immune disease pathogenesis and design of novel therapies.