Immature Dendritic Cells Suppress Collagen-Induced Arthritis by In Vivo Expansion of CD49b+ Regulatory T Cells

Abstract

Dendritic cells (DCs) are specialized APCs with an important role in the initiation and regulation of immune responses. Immature DCs (iDCs) reportedly mediate tolerance in the absence of maturation/inflammatory stimuli, presumably by the induction of regulatory T cells. In this study, we show for the first time that repetitive iDC injections trigger the expansion of a novel regulatory population with high immunomodulatory properties, able to protect mice from collagen-induced arthritis. These regulatory T cells are characterized by the expression of the CD49b molecule and correspond to a CD4+ α-galactosylceramide/CD1d-nonrestricted T cell population producing IL-10. Adoptive transfer of <105 TCRβ+CD49b+ cells isolated from the liver of iDCs-vaccinated mice, conferred a complete protection against arthritis. This protection was associated with an attenuation of the B and T cell response associated with a local secretion of IL-10. Thus, together these data demonstrate that iDCs can expand and activate a novel regulatory population of CD49b+ T cells, with high immunosuppressive potential able to mediate protection against a systemic autoimmune disease.

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

“…Because vaccination with 1 ϫ 10 6 tolerogenic DCs was not sufficient to cure disease, we increased the dose of tolerogenic DCs to 2.5 ϫ 10 6 per vaccination, a dose that is sufficient to prevent CIA using TNF-treated tolerogenic DCs (18)(19)(20). However, there is a risk involved in increasing the dose of tolerogenic DCs: another study showed that a dose of 2.5 ϫ 10 6 TNF-treated DCs was pathogenic (22).…”

“…For instance, DCs transduced with FasL or IL-4 have been used to prevent CIA and to inhibit arthritis symptoms in mice with established disease (15)(16)(17). Tolerogenic DCs modified by drugs (dexamethasone; Bay 11-7082) or cytokines (tumor necrosis factor [TNF]) have been used successfully to prevent the onset of CIA (18)(19)(20)(21)(22) or to suppress established arthritis in a different model, the antigeninduced arthritis model (23).…”

In vivo RNAi-mediated silencing of TAK1 decreases inflammatory Th1 and Th17 cells through targeting of myeloid cells

“…Starting at day 21, paw thickness was measured 3 times a week with a Mitutoyo micrometer (Sigma-Aldrich), and the severity of arthritis was graded by macroscopic examination as previously described. 23 After euthanasia, the knee joints were collected and incubated for 24 hours in RPMI 1640 (300 L). Supernatants were stored until quantification of cytokines by enzyme-linked immunosorbent assay (ELISA).…”

Dendritic cells in tolerance induction for the treatment of autoimmune diseases

“…The mechanisms are, however, different in that IL-10 DC skew the response toward Th2 polarization, while DX-DC inhibit Th1 development by inducing IL-10-producing T cells [59]. Also collagen II-loaded, non-manipulated immature DC can inhibit CIA via the expansion of Treg [60]. One important issue to be considered is the number of injected DC: TNF-a-DC have been shown to be effective in inhibiting CIA and in inducing Treg only when injected at low doses (10 5 cells) [61].…”