Targeting vaccines to dendritic cells A functional analysis of human XCL1 and XCL2 in mice

Abstract

The idea of targeting vaccines directly to antigen presenting cells to increase vaccine efficiency has received great attention in recent years, and so has the strategy of further tailoring the vaccine to elicit a desired immune response. Several targeting strategies are currently being tested, including the use of monoclonal antibodies and natural ligands of cell surface receptors. In mice, CD8α+ dendritic cells are known to be especially good at inducing CD8+ T-cell responses against extracellular antigens (cross-priming). These cells exclusively express the chemokine (C motif) receptor 1, Xcr1. Interestingly, recent studies have found a homologous DC population in humans that express a human version of this receptor. There are two human homologues of the murine chemokine (C motif) ligand 1 Xcl1, hXCL1 and the closely related hXCL2. In the first part of this project we show that the human chemokine hXCL1 binds murine Xcr1+ cells, and that the use of hXCL1 and hXCL2 to target the influenza antigen hemagglutinin (HA) towards Xcr1+ cells gives protective immune responses in mice. In contrast to other chemokines, hXCL1 is known to exist in two conformations under physiological conditions, a monomeric receptor binding conformation and a dimeric conformation binding glycosaminoglycans (GAGs). In the second part of this project we show that stabilizing the monomeric receptor binding conformation also results in binding of the Xcr1 receptor and immune responses in mice. This stabilization might be advantageous in a targeted vaccine setting, as it might increase the efficiency of the vaccine. Our results suggest that there is conservation between species with regards to this receptor-ligand pair, and that the use of hXCL1/2 in targeting to antigen presenting cells may be transferable to humans.