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A8.19 Non-lymphoid CD103+ dendritic cells are required for the initiation of collagen-induced arthritis
  1. M I Ramos1,2,
  2. S Garcia1,2,
  3. W Baum3,
  4. B Helder1,2,
  5. S Aarrass1,2,
  6. K A Reedquist1,2,
  7. G Schett3,
  8. P P Tak*,1,
  9. M C Lebre1,2
  1. 1Amsterdam Rheumatology & Immunology Center
  2. 2Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands;
  3. 3Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  4. *Current affiliations: Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands, University of Cambridge, UK and GlaxoSmithKline, Stevenage, UK


Background and Objectives Dendritic cells (DCs) are essential for the initiation of synovial inflammation, but it is unclear which subset of DCs performs this task. We have shown that FMS-like tyrosine kinase 3 ligand (Flt3L)-dependent DCs are important for disease development in a mouse model for RA. However since Flt3L-/- mice have reductions in all conventional (c)DCs it remained unclear which subset is required for disease induction.

Materials and Methods CIA was induced in Flt3L-/-, Batf3-/- (mice lacking both CD103+ and CD8a+DCs) and WT C57/BL6 littermates. In vitro and in vivo uptake and migration was performed using bone marrow (BM)-DCs and dermal DCs. Antigen presentation was studied in vivo by adoptive transfer of CFSE-labeled OT-I or OT-II T cells + OVA in Flt3L-/- and WT mice and in vitro by culturing BM-DCs with OT-I and OT-II cells. T cell proliferation was analysed by CFSE dilution. To study BM-DC function qPCR array (Dendritic and Antigen Presenting Cell PCR Array- Qiagen) for 84 genes was performed. To test the potential of a Flt3 inhibitor (CEP701) in the prevention of CIA, an in vivo study was performed injecting CEP701 before the onset of disease in DBA-1 mice.

Results Flt3L-/- mice were susceptible to innate K/BxN arthritic model and arthritic T cell transfer. Batf3-/- mice lacking both CD103 + and CD8a + DCs were resistant to CIA, demonstrating that CD11b + and monocyte-derived DCs (moDCs) were not sufficient to induce CIA. The amount of DCs carrying antigen reaching the LN in Flt3L-/- mice was reduced compared with WT. Uptake and migratory capacity was similar in Flt3L-/- BM-DCs compared to WT BM-DCs. CEP701 (a Flt3L inhibitor) treatment prevented CIA induction, and reduced dramatically CD103 + DCs in the lymph nodes and synovium. Human CD141hi DCs, homologues of mouse CD103 + DCs, were present and increased in inflamed rheumatoid arthritis (RA) synovium.

Conclusions Antigen presentation in Flt3L-/- mice is impaired. As CD103 + DCs are absent in Flt3L-/- mice and are important in (cross)-presenting antigens our data reveals a crucial role for CD103 + DCs in the induction of CIA. As a consequence of CD103 + DC absence Flt3L-/- mice showed a reduction in T cell activation in particularly reduced CD8 T cell responses. Hence this study identified non-lymphoid CD103 + DCs as the main subset orchestrating the initiation of cell-mediated immunity in arthritis. Targeting this DC subset might be of interest in individuals at risk of developing autoimmune disorders.

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