Cooperative stimulation of dendritic cells by Cryptococcus neoformans mannoproteins and CpG oligodeoxynucleotides.
While mannosylation targets antigens to mannose receptors on dendritic cells (DC), the resultant immune response is suboptimal. We hypothesized that the addition of toll-like receptor (TLR) ligands would enhance the DC response to mannosylated antigens. Cryptococcus neoformans mannoproteins (MP) synergized with CpG-containing oligodeoxynucleotides to stimulate enhanced production of proinflammatory cytokines and chemokines from murine conventional and plasmacytoid DC. Synergistic stimulation required the interaction of mannose residues on MP with the macrophage mannose receptor (MR), CD206. Moreover, synergy with MP was observed with other TLR ligands, including tripalmitoylated lipopeptide (Pam3CSK4), polyinosine-polycytidylic acid (pI:C), and imiquimod. Finally, CpG enhanced MP-specific MHC II-restricted CD4(+) T-cell responses by a mechanism dependent upon DC expression of CD206 and TLR9. These data suggest a rationale for vaccination strategies that combine mannosylated antigens with TLR ligands and imply that immune responses to naturally mannosylated antigens on pathogens may be greatly augmented if TLR and MR are cooperatively stimulated.
Dan
Jennifer M
JM
Department of Microbiology and Immunology Training Program, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Wang
Jennifer P
JP
Lee
Chrono K
CK
Levitz
Stuart M
SM
D000818:Animals; D002451:Cell Compartmentation / Q000187:drug effects; D018925:Chemokines / Q000096:biosynthesis; D003455:Cryptococcus neoformans / Q000737:chemistry*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects*; D006825:Hybridomas; D018836:Inflammation Mediators / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology; D008024:Ligands; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects; D051193:Toll-Like Receptors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C408982:CPG-oligonucleotide; D018925:Chemokines; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D008024:Ligands; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C025363:mannoproteins