Type 1 interferon-producing cells (IPCs), also known as plasmacytoid dendritic cells (pDCs), have the capacity to rapidly produce a large amount of type-1 IFNs following viral stimulation. pDCs play critical roles in controlling the function of NK cells, myeloid DCs and B cells through type 1-IFNs (innate phase). After the innate phase of immune responses, pDCs undergo a functional switch from professional type 1 IFNproducing cells to professional antigen presenting mature DCs that are able to activate and regulate T cell responses (adaptive phase). Depletion of pDC/IPC was found to be associated with uncontrolled viral infection and over-activation of pDC/IPCs was found to be associated with the pathogenesis of autoimmune diseases such as systemic lupus erythematosus and psoriasis. Targeting TLR9 or TLR7 expressed on pDC leads to strong pDC activation, which promotes the function of mDC, NK cells and B cells in anti-viral or antitumor immune responses. Although the majority of the current studies on pDCs have been focused on type 1 IFNs, our recent microarray gene expression analysis reveals for the first time that pDCs not only rapidly express more than 20 different type 1 IFN subtypes (Ito T et al, Blood, 2005), but also express high levels of more 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 the expression of the corresponding TNFR family members in all human immune cell types, and thus establishes a potentially new immunological network between pDCs to mDCs, pDC to NK cells and pDC to B cells through members of the TNF and TNFR superfamily. The expression of TNF/TNFR family members by human 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, a case 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 TNF superfamily expressed by activated pDCs play distinct and synergistic roles in responding to viral infection. Establishing the molecular mechanisms and networks by which pDC sense viral infection and communicate with other cell types within the immune system will generate great value in targeting pDC either negatively for blocking autoimmune diseases or positively for the development of more effective vaccine 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 cell mediated 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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