Submitted June 15, 2007
Accepted November 17, 2007
Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a-C3aR interaction
Qi Peng, Ke Li, Katie Anderson, Conrad A. Farrar, Bao Lu, Richard A.G. Smith, Steven H Sacks, and Wuding Zhou*
MRC Centre for Transplantation and Department of Nephrology and Transplantation, King's College London, London, United Kingdom
Division of Pulmonary Medicine and Ina Sue Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, MA, United States
* Corresponding author; email: wuding.zhou{at}kcl.ac.uk.
Donor cell expression of C3 enhances the alloimmune response and is associated with the fate of transplantation. In order to clarify the mechanism for enhancement of the immune response, we have explored the role of C3a receptor (C3aR)-ligand interaction on murine bone marrow dendritic cells (DCs). We show that DCs either lacked receptor for C3a (a C3 cleavage product) or were treated with C3aR antagonist, elicited defective T cell priming against alloantigen expressed on the DCs. This was associated with reduced surface expression of MHC and co-stimulatory molecules on the DCs, and with defective priming in skin allograft rejection. In addition, DCs lacking factor B were unable to generate potent T cell responses against donor antigen, while lack of C4 had no detectable effect, suggesting a role for the alternative pathway contributing to allostimulation. Furthermore, therapeutic complement regulator can down-regulate DC allostimulatory function. These findings suggest that the capacity of DCs for allostimulation depend on their ability to express, activate and detect relevant complement components leading to C3aR signalling. This mechanism, in addition to underpinning the cell-autonomous action of donor C3 on allostimulation, has implications for a wider range of immune responses in self-restricted T cell priming.
