Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a-C3aR interaction.
Donor cell expression of C3 enhances the alloimmune response and is associated with the fate of transplantation. 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 major histocompatibility complex (MHC) and costimulatory 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, whereas 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 depends on their ability to express, activate, and detect relevant complement components leading to C3aR signaling. 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.
Medical Research Council Centre for Transplantation, Department of Nephrology and Transplantation, King's College London, London, United Kingdom.
Qi
Q
Peng
Ke
K
Li
Katie
K
Anderson
Conrad A
CA
Farrar
Bao
B
Lu
Richard A G
RA
Smith
Steven H
SH
Sacks
Wuding
W
Zhou
D000818:Animals; D003167:Complement Activation; D015926:Complement C3a / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000502:physiology* / Q000637:transplantation*; D006084:Graft Rejection / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D016177:Macrophage-1 Antigen; D015926:Complement C3a