Background Dendritic cells (DCs) are a heterogeneous population of antigen-sensing and-presenting cells that play an important role for the initiation of protective and pathogenic immunity. Flt3L is a growth factor that can drive DC development from bone marrow (BM) progenitors and it is crucial for steady-state DC maintenance. Collagen-induced arthritis (CIA) induction requires dermal DC uptake, processing, migration and presentation of antigen to lymph node (LN) T cells.
Objectives The objective of this study was to find the mechanism of protection in CIA observed in mice lacking Flt3L (Flt3L-/-).
Methods CIA was induced in Flt3L-/- and WT littermates. The severity of the arthritis was assessed using an established semiquantitative scoring system (0–4). In vitro uptake and migration was assessed by using BM-DC (differentiated with GM-CSF for 9 days). OVA-FITC was injected intradermally in Flt3L-/- and WT animals, after 36h LNs were collected and the number of FITC positive cells was determined. Antigen presentation was studied by adoptive transfer of CFSE-labeled OT-I or OT-II T cells + OVA (i.d.) into Flt3L-/- and WT animals. After 3 days LNs were collected and T cell proliferation was analyzed by CFSE dilution.
Results Flt3L-/- mice (steady-state) have severe reductions in DC populations in lymphoid and non-lymphoid organs. Flt3L-/- mice are protected from CIA showing impaired T and B cell responses. Flt3L-/- mice have reduced dermal CD11b+ DCs and CD103+ DCs are almost absent. In addition, the amount of DCs carrying antigen reaching the LN in Flt3L-/- mice was reduced compared with WT. In vitro and in vivo experiments using BMDCs demonstrated that Flt3L-/- BMDCs have the same capacity to uptake and migrate as WT BMDCs. Moreover, adoptive transfer of OT-I and OT-II T cells + OVA in Flt3L-/- mice resulted in a dramatic reduction of total cell proliferation and more importantly less divisions compared with WT animals. FACS analysis of WT and Flt3L-/- mice synovium at the acute phase of CIA showed that CD11b+ DC are present and increased in arthritic animals compared with immunized but not arthritic animals. CD103+DC are only present in WT animals, and increased in animals with a high clinical score.
Conclusions Our data shows that antigen presentation in Flt3L-/- mice is impaired. As CD103+ DC are important in presenting and cross-presenting antigens our data reveals an important role for CD103+ DC in both induction and maintenance of CIA. Specifically targeting CD103+ DC could provide a novel anti-rheumatic strategy.
Disclosure of Interest M. Ramos: None Declared, S. Aarrass: None Declared, S. Jacobsen: None Declared, P. Tak Employee of: GlaxoSmithKline, Stevenage, U.K., M. C. Lebre: None Declared