Selective elimination of dendritic cells
Selective elimination of dendritic cells for immunological manipulation in infection, transplantation and autoimmunity
Cross-presentation as a fundamental pathway of activating CD8+ T cells has been well established. So far, the application of this concept in vivo is limited. Here, we take advantage of the specific cytosolic export feature of cross-presenting dendritic cells (DCs) together with the property of cytosolic cytochrome c (cytc) in initiating Apaf-1-dependent apoptosis. Thus cytc should selectively kill cross-presenting DCs. Intravenous injection of cytc produced a 2-3-fold reduction in splenic CD8+ DCs. It abolished the induction of cytotoxic T lymphocytes (CTL) to exogenous antigen and reduced subsequent immunity to tumour challenge. Our model opens an avenue to specifically target cross-presenting DCs in vivo for manipulating CTL responses toward infections, tumors, transplants and autoimmune diabetes.
We are also analysing the role of various DCs (not just cross-presenting ones) during transplantation and during autoimmune diabetes.
Horse cytc-mediated apoptosis of cross-presenting DCs within the CD8+ DC population.
Figure legend: FACS of splenic DCs 24h after injection with 5mg of horse or yeast cytc. Note that yeast cytc binds poorly to Apaf-1 so is not apoptogenic. Numbers indicate the relative % of CD11c+ cells.