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Originally published online as doi:10.1189/jlb.0608374 on November 6, 2008

Published online before print November 6, 2008
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(Journal of Leukocyte Biology. 2009;85:243-250.)
© 2009 The Author(s)

LPS activation is required for migratory activity and antigen presentation by tolerogenic dendritic cells

Amy E. Anderson, David J. Swan, Bethan L. Sayers, Rachel A. Harry, Angela M. Patterson1, Alexei von Delwig, John H. Robinson, John D. Isaacs and Catharien M. U. Hilkens2

Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

2 Correspondence: Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Catherine Cookson Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. E-mail: catharien.hilkens{at}newcastle.ac.uk

ABSTRACT

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.

Key Words: tolerance • migration • CCR7 • naïve T cells • immunotherapy




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