Structural Requirements Of B7 Ligands For Regulation Of Indoleamine 2,3-Dioxygenase In Dendritic Cells

Ligation of B7-1 and B7-2 by CTLA-4 has been shown to upregulate the immunomodulatory enzyme, indoleamine 2,3 –dioxygenase (IDO), in various subsets of dendritic cells. In particular, functional expression of IDO in CD8α+CD11c+ and CD19+B220+CD11c+ plasmacytoid dendritic cells (pDCs) leads to suppression of T cell function. In pDCs, upregulation of IDO upon B7 ligation has been suggested to be mediated via type I IFN signaling. In contrast, in CD8α+CD11c+B220− non-pDCs induction of IDO following binding of CTLA-4 to B7 ligands requires autocrine effects of IFN-γ, recruitment of STAT-1, and involves p38MAPK and NF-κB. Numerous studies have thus demonstrated that the reverse signaling through B7 in dendritic cells represents an important mechanism for the regulation of T cell activation and tolerance. However, the structural determinants of B7 which are important for signaling have not been identified. As an initial strategy to this end, we have generated a library of genetically engineered mice that express B7, either full length or without the cytoplasmic tail, on various subsets of dendritic cells. Our studies show that the development of splenic pDCs and non-pDCs is not impaired by the absence of cytoplasmic tail of B7 ligands. Ongoing studies are characterizing the functional consequences of absence of B7 cytoplasmic tail on CTLA-4 mediated IDO upregulation in dendritic cells.