365 Myeloid but not plasmacytoid blood DCs possess Th1 polarizing and Th1/Th17 recruiting capacity in psoriasis

Abstract

In order to suppress self-reactive T cells that escape from central tolerance, additional mechanism in peripheries, so-called peripheral tolerance, is essential; however this mechanism is not fully elucidated. To investigate this issue, here we generated a novel murine transgenic line that expressed membrane-bound ovalbumin (mOVA) under the control of human involucrin (Ivl) promoter; Ivl-mOVA mice. Within one week after the transfer of CD8 + T cells from OT-I mice (OT-I T cells), GVHD-like cutaneous and mucosal eruptions developed. Histological analysis revealed massive infiltration of OT-I T cells to the epidermis. Intriguingly, most (>95%) of the transferred OT-I T cells were deleted in lymph nodes within 24 h, and subsequent extensive expansion of OT-I T cells was observed 48 h post transfer. This expansion was observed not only in skin-draining lymph nodes but also in mesenteric lymph nodes, spleen, and bone marrow. We used bone-marrow chimeric mice reconstituted with b2-microglobulin-deficient mice, which lack functional MHC class I, to identify the responsible cell subset for initial deletion of OT-I T cells. OT-I T cell deletion was observed even in these chimeric mice. This result indicates the essential role of radio-resistant cells, suggestive of stromal cells, in secondary lymphoid organs. Taken together, these results suggest that tissue-specific self-antigens presented by radio-resistant lymph node stromal cells control peripheral tolerance and development of GVHD-like skin lesion. 365Myeloid but not plasmacytoid blood DCs possess Th1 polarizing and Th1/Th17 recruiting capacity in psoriasis A Psoriasis is a common inflammatory skin disease and dendritic cells (DCs) play a crucial role in the development of skin inflammation. Although the characteristics of skin DCs in psoriasis are well defined, less is known about their peripheral blood precursors. Our aim was to characterize the phenotypic features as well as the cytokine and chemokine production of CD1c+ myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the blood samples of psoriatic patients. Blood DCs were isolated by using a magnetic separation kit, and their intracytoplasmic cytokine production and CD83/CD86 maturation/activation marker expression were investigated by 8-colour flow cytometry. In CD1c+ mDCs, the intracellular productions of Th1, Th2, Th17, Th22 and Treg polarizing cytokines were examined simultaneously, whereas in pDCs the amounts of IFNa, as well as IL-12, IL-23, and IL-6, were investigated. The chemokine production of both DC populations was investigated by flow cytometry and ELISA. According to our results, psoriatic CD1c+ mDCs were in a premature state since their CD83/CD86 maturation/activation marker expression, IL-12 cytokine, CXCL9 and CCL20 chemokine production was significantly higher compared to control cells. On the other hand, blood pDCs neither produced any of the investigated cytokines and chemokines nor expressed CD83/CD86 maturation/activation markers. Our results indicate that in psoriasis not only skin but al...