LPS activation is required for migratory activity and antigen presentation by tolerogenic dendritic cells.
Autoimmune pathologies are caused by a breakdown in self-tolerance. Tolerogenic dendritic cells (tolDC) are a promising immunotherapeutic tool for restoring self-tolerance in an antigen-specific manner. Studies about tolDC have focused largely on generating stable maturation-resistant DC, but few have fully addressed questions about the antigen-presenting and migratory capacities of these cells, prerequisites for successful immunotherapy. Here, we investigated whether human tolDC, generated with dexamethasone and the active form of vitamin D3, maintained their tolerogenic function upon activation with LPS (LPS-tolDC), while acquiring the ability to present exogenous autoantigen and to migrate in response to the CCR7 ligand CCL19. LPS activation led to important changes in the tolDC phenotype and function. LPS-tolDC, but not tolDC, expressed the chemokine receptor CCR7 and migrated in response to CCL19. Furthermore, LPS-tolDC were superior to tolDC in their ability to present type II collagen, a candidate autoantigen in rheumatoid arthritis. tolDC and LPS-tolDC had low stimulatory capacity for allogeneic, naïve T cells and skewed T cell polarization toward an anti-inflammatory phenotype, although LPS-tolDC induced significantly higher levels of IL-10 production by T cells. Our finding that LPS activation is essential for inducing migratory and antigen-presenting activity in tolDC is important for optimizing their therapeutic potential.
Anderson
Amy E
AE
Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Swan
David J
DJ
Sayers
Bethan L
BL
Harry
Rachel A
RA
Patterson
Angela M
AM
von Delwig
Alexei
A
Robinson
John H
JH
Isaacs
John D
JD
Hilkens
Catharien M U
CM
D000893:Anti-Inflammatory Agents / Q000378:metabolism; D017951:Antigen Presentation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D054415:Chemokine CCL19 / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007155:Immunologic Factors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D010641:Phenotype; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000893:Anti-Inflammatory Agents; D054415:Chemokine CCL19; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine