A conformationally-biased, response-selective agonist of C5a acts as a molecular adjuvant by modulating antigen processing and presentation activities of human dendritic cells.
A partial mechanism by which a conformationally-biased, response-selective agonist of complement component C5a, Tyr-Ser-Phe-Lys-Pro-Met-Pro-Leu-D-Ala-Arg or YSFKPMPLaR (EP54), acts as a molecular adjuvant is presented by showing the manner in which this peptide engages human dendritic cells (DC). Confocal microscopy was used to show that fluorescent-labeled EP54 (0.2 microM) and fluorescent-labeled B and T cell epitopes attached to EP54 (i.e., EP54-containing vaccines, 0.2 microM) were internalized by human DCs well within 30 min of exposure. After 24 h of exposure, EP54 and the B and T cell epitopes of the EP54-containing vaccines (20 microM) were presented on the DC surface in the context of HLA-ABC and HLA-DR determinants. Also, exposure of DCs to EP54 (50 microg/ml) induced the activation of genes specific for the Th1 cytokines IL-6, IL-12, INFgamma, and TNFalpha as well as the Th2 cytokine IL-4. Internalization, HLA expression, and cytokine gene activation were not observed in the presence of the inactive, scrambled EP54 constructs arguing that these effects of EP54 are mediated predominately via C5a receptors on the DC surface.
Hegde
Ganapati V
GV
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Meyers-Clark
Erin
E
Joshi
Shantaram S
SS
Sanderson
Sam D
SD
D000276:Adjuvants, Immunologic; D017951:Antigen Presentation; D015936:Complement C5a / Q000819:agonists* / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018985:Epitopes, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D016207:Cytokines; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; C105322:complement C5a, (65-74), Tyr(65)-Phe(67)-Pro(69,71)-Ala(73)-; D015936:Complement C5a