Selective depletion of CD11c+CD11b+ dendritic cells partially abrogates tolerogenic effects of intravenous MOG in murine EAE

Intravenous (i.v.) injection of a soluble myelin antigen can induce tolerance, which effectively ameliorates experimental autoimmune encephalomyelitis (EAE). We have previously shown that i.v. MOG induces tolerance in EAE and expands a subpopulation of tolerogenic CD11c⁺CD11b⁺ dendritic cells (DCs) with an immature phenotype having low expression of IA and co-stimulatory molecules CD40, CD86, and CD80. Here we further investigate the role of tolerogenic DCs in i.v. tolerance by injecting clodronate-loaded liposomes, which selectively deplete CD11c⁺CD11b⁺ and immature DCs, but not CD11c⁺CD8⁺ DCs and mature DCs. I.v. MOG-induced suppression of EAE was partially, yet significantly, blocked by CD11c⁺CD11b⁺ DC depletion. While i.v. MOG inhibited IA, CD40, CD80, CD86 expression and induced TGF-β, IL-27, IL-10 production in CD11c⁺CD11b⁺ DCs, these effects were abrogated after injection of clodronate-loaded liposomes. Depletion of CD11c⁺CD11b⁺ DCs also precluded i.v. autoantigen-induced T-cell tolerance, such as decreased production of IL-2, IFN-γ, IL-17 and numbers of IL-2⁺, IFN-γ⁺, and IL-17⁺ CD4⁺ T cells, as well as an increased proportion of CD4⁺CD25⁺Foxp3⁺ regulatory T cells and CD4⁺IL-10⁺Foxp3⁻ Tr1 cells. CD11c⁺CD11b⁺ DCs, through low expression of IA and co-stimulatory molecules as well as high expression of TGF-β, IL-27 and IL-10, play an important role in i.v. tolerance-induced EAE suppression.

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