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

Abstract

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.

Dendritic Cells As Inducers of Peripheral Tolerance

“…However, a similar ablation of DCs did not always cause a disturbed homeostasis of peripheral T cells [66], possibly reflecting differences in deletion of specific DC populations in addition to complex physiologic conditions associated with the uptake of self-antigens and a subsequent activation of self-reactive T cells, as discussed above. Nevertheless, in other experimental systems including specific DTR expression in either chemokine receptor (XCR1) + DCs or in the entire DC lineage controlled by the transcription factor Zbtb46, as well as in experiments that relied on a chemical depletion of some DCs, the absence of DCs or their subsets disturbed tolerance and immune homeostasis [27, 28, 67]. …”

Harnessing the properties of dendritic cells in the pursuit of immunological tolerance

“…Selective depletion of CD11c + CD11b + DCs and immature DCs with the use of clodronate-loaded liposomes significantly blocks the disease suppressing effects of intravenous soluble MOG administration, as measured by clinical scoring. Depletion of these tol-DCs was associated with a loss of MOG-induced T cell tolerance, normally characterised by an increase in prevalence of FoxP3 + cells and decreased production of the inflammatory cytokines IL-2, IFN-γ and IL-17 [91] .…”

A unique tolerizing dendritic cell phenotype induced by the synthetic triterpenoid CDDO-DFPA (RTA-408) is protective against EAE

“…Antigen-presenting cells (APCs) or dendritic cells (DCs) are central players in the development and maintenance of immunity and tolerance 1 – 3 . Efforts to exploit their potential as cellular therapies range from the induction of tumor immunity to the establishment of transplant tolerance and the suppression of autoimmunity 4 – 6 .…”