Type 1 interferon-producing cells (IPCs), also known as plasmacytoid dendritic cells (pDCs), have thecapacity to rapidly produce a large amount of type-1 IFNs following viral stimulation. pDCs play critical rolesin controlling the function of NK cells, myeloid DCs and B cells through type 1-IFNs (innate phase). After theinnate phase of immune responses, pDCs undergo a functional switch from professional type 1 IFNproducingcells to professional antigen presenting mature DCs that are able to activate and regulate T cellresponses (adaptive phase). Depletion of pDC/IPC was found to be associated with uncontrolled viralinfection and over-activation of pDC/IPCs was found to be associated with the pathogenesis of autoimmunediseases such as systemic lupus erythematosus and psoriasis. Targeting TLR9 or TLR7 expressed on pDCleads to strong pDC activation, which promotes the function of mDC, NK cells and B cells in anti-viral or antitumorimmune responses. Although the majority of the current studies on pDCs have been focused on type 1IFNs, our recent microarray gene expression analysis reveals for the first time that pDCs not only rapidlyexpress more than 20 different type 1 IFN subtypes (Ito T et al, Blood, 2005), but also express high levels ofmore than 9 different co-stimulatory molecules within the TNF super-family members, including TNF-a, LT-a,OX40L, 4-1BBL, CD27L (CD70), GITRL, TRAIL, BAFF and APRIL. The microarray data also reveal theexpression of the corresponding TNFR family members in all human immune cell types, and thus establishesa potentially new immunological network between pDCs to mDCs, pDC to NK cells and pDC to B cellsthrough members of the TNF and TNFR superfamily. The expression of TNF/TNFR family members byhuman immune cell types at the mRNA levels is now further confirmed at the protein levels by flowcvtometrv.We further show that GITRL expressed by pDCs activated through TLR9 costimulates NK cell activation, acase study demonstrating our ability to translate the microarrav data into protein and functional data(Hanabuchi S. Blood 2006). Our central hypothesis is that type 1 IFNs and members of the TNFsuperfamily expressed by activated pDCs play distinct and synergistic roles in responding to viralinfection. Establishing the molecular mechanisms and networks by which pDC sense viral infection andcommunicate with other cell types within the immune system will generate great value in targeting pDCeither negatively for blocking autoimmune diseases or positively for the development of more effectivevaccine for cancer and infectious diseases. Accordingly, the specific aims of this proposal are:> Aim 1. To investigate the molecular interactions between pDC and mDCs in regulating T cellmediated immune responses> Aim 2. To investigate the molecular interactions between pDC and NK cells> Aim 3. To investigate the molecular interactions between pDCs and B lymphocytes
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