Abstract
Abstract 1746
Dendritic cells (DC) initiate and direct immune responses. Plasmacytoid DC (pDC) produce type I interferon (IFN) in response to viral and/or bacterial challenge and have been implicated in the pathogenesis of a number of chronic inflammatory disesases. pDC also induce the generation of regulatory T cells (Treg) from naïve CD4+ T cells. Treg control the balance of T cell responses and maintain immune homeostasis so the primary contribution of pDC to Treg induction in disease states is an important question. Psoriasis is a common chronic inflammatory skin disease associated with over expression of type I IFN–inducible genes in patients and this response apparently overwhelms any pDC regulatory contribution. The numbers of peripheral blood Treg cells and pDC are decreased in psoriatic patients but why pDC fail to generate a significant counterbalancing Treg response in psoriasis is unknown.
We compared purified blood pDC from normal donors with those from psoriasis donors, who were well and either untreated or only on topical therapy at the time of donation, for their ability to induce Treg. Freshly purified pDC from both normal and psoriasis donors lacked CD80 and CD83, but expressed similar amounts of HLA-DR and CD86. pDC from healthy psoriasis donors, when stimulated with TLR9 ligands, secreted high amounts of IL-6, expressed little surface inducible costimulator-ligand (ICOS-L, CD275) and exhibited low indoleamine 2, 3–dioxygenase (IDO) enzymatic activity compared to normal controls. To assess the capacity of pDC from psoriasis patients to induce the differentiation of naïve CD4+ T cells, we performed sequential co-culture experiments. In these, TLR-9 stimulated pDC from psoriasis patients failed to induce the differentiation of naïve CD4+ T cells into IL-10 secreting, functional regulatory T cells. In addition, the CD4+CD25+ T cells resulting from co-culture with psoriasis pDC were less effective in suppressing an allogeneic MLR. In contrast, the pDC from psoriasis patients, unlike those from normal donors, induced T cells capable of secreting IL-22. Further investigation as to why psoriatic pDC failed to induce Treg showed that the differentiated CD4+CD25+ (CD127-) T cells from these co-cultures expressed dramatically less Foxp3 following priming with psoriatic pDC. Exogenous kynurenine, to replace IDO restored the ability of psoriatic pDC to induce Treg.
In conclusion, our data demonstrate that aberrant pDC produce dysfunctional Treg development in psoriasis and highlights the contributions of IL-6/IDO/CD275/IL-22 to the disease pathogenesis. This insight is now driving studies in other disease states, notably graft versus host disease, where our focus is on manipulating DC for therapeutic benefit.
Disclosures:
No relevant conflicts of interest to declare.
Dendritic Cells With TGF-β1 and IL-2 Differentiate Naive CD4+ T Cells Into Alloantigen-Specific and Allograft Protective Foxp3+ Regulatory T Cells