Abstract
Objective: Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3+ regulatory T cells (Treg), which in turn exert immunosuppression by increasing TGFβ-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2-/-) mice had impaired DCs migration and reduced CD8α+ DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2-/- mice, we tested the hypothesis that CD8α+ DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8α+ DCs in Ccr2-/- and SKG mice. Methods: To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8α+ DCs. Results: Flt3L-mediated expansion of endogenous CD8α+ DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8α+ DCs ameliorated arthritis in Ccr2-/- mice and enhanced TGFβ1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype. Conclusion: CD8α+ DCs were tolerogenic to the development of arthritis. CD8α+ DCs deficiency heightened the sensitivity to arthritis in Ccr2-/- mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2-/- mice was T cell-independent.
Original language | English (US) |
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Pages (from-to) | 971-978 |
Number of pages | 8 |
Journal | Immunobiology |
Volume | 216 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2011 |
Keywords
- Arthritis
- CCR2
- CD8α DC
- Dendritic cells
- SKG
ASJC Scopus subject areas
- Hematology
- Immunology and Allergy
- Immunology