LPS activation is required for migratory activity and antigen presentation by tolerogenic dendritic cells

Abstract

Autoimmune pathologies are caused by a breakdown in self-tolerance. Tolerogenic dendritic cells (tolDC) are a promising immunotherapeutic tool for restoring self-tolerance in an antigen-specific manner. Studies about tolDC have focused largely on generating stable maturation-resistant DC, but few have fully addressed questions about the antigen-presenting and migratory capacities of these cells, prerequisites for successful immunotherapy. Here, we investigated whether human tolDC, generated with dexamethasone and the active form of vitamin D3, maintained their tolerogenic function upon activation with LPS (LPS-tolDC), while acquiring the ability to present exogenous autoantigen and to migrate in response to the CCR7 ligand CCL19. LPS activation led to important changes in the tolDC phenotype and function. LPS-tolDC, but not tolDC, expressed the chemokine receptor CCR7 and migrated in response to CCL19. Furthermore, LPS-tolDC were superior to tolDC in their ability to present type II collagen, a candidate autoantigen in rheumatoid arthritis. tolDC and LPS-tolDC had low stimulatory capacity for allogeneic, naïve T cells and skewed T cell polarization toward an anti-inflammatory phenotype, although LPS-tolDC induced significantly higher levels of IL-10 production by T cells. Our finding that LPS activation is essential for inducing migratory and antigen-presenting activity in tolDC is important for optimizing their therapeutic potential.

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

“…Interestingly, human tolDC, generated with dexamethasone and the active form of vitamin D3, were shown not only to maintain their tolerogenic function upon activation with maturation stimuli (LPS) but were superior in terms of their migratory activity toward CCL19 (confirmed in our report72) and had enhanced antigen‐presenting ability 23. Citrullinated‐peptide‐pulsed tolDC have also been reported to be safe and effective in a Phase 1 clinical study in patients with rheumatoid arthritis 13.…”

“…However, phenotypic characterization alone is insufficient to determine whether DC will induce tolerance or immunity 21, 22. In addition, it has been suggested that irrespective of the desired therapeutic outcome (induction of tolerance for prevention of autoimmune disease or immunity for treatment of cancer) DC activation is essential for the effectiveness of immunotherapy as activated DC preferentially migrate from the peripheral tissues into the draining lymph nodes where antigen‐specific interaction with T cells occurs 23, 24, 25…”

1,25-Dihydroxyvitamin D3 Promotes Tolerogenic Dendritic Cells with Functional Migratory Properties in NOD Mice

“…Notably, activation through TLR4 is essential for DCs to acquire a functional migratory capacity. Therefore, it is conceivable that Ctr-mDCs would have a greater ability to migrate in vivo, because treatment with 1,25(OH) 2 D 3 counteracts several aspects of DC activation/maturation following exposure to such TLR stimuli (55). Strikingly, we show that NOD-derived 1,25D 3 -mDCs exhibited increased functional capacity to migrate to the pancreas and liver of recipient adult NOD compared with Ctr-mDCs.…”

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

“…Treatment of DCs with 1␣,25-dihydroxyvitamin D 3 (vitamin D 3 ) in combination with dexamethasone has been shown to synergistically inhibit lipopolysaccharide (LPS)-induced maturation of DCs (24). Previously, we used these immunosuppressive drugs to generate human tolerogenic DCs with potent immunoregulatory function in vitro (25,26). An important outstanding question is, however, whether these pharmacologically modified tolerogenic DCs can inhibit pathogenic IL-17-mediated responses in vivo, and whether they will be effective at reducing the progression and severity of arthritis when administered after disease onset.…”