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Induction of Th17 responses by human skin dendritic cells is dependent on IL‐15 and IL‐6
Author(s) -
Mathers Alicia R,
Janelsins Brian M,
Rubin Joseph P,
Tkacheva Olga A,
Larregina Adriana T
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.846.26
Subject(s) - microbiology and biotechnology , effector , secretion , immunology , autoimmunity , proinflammatory cytokine , inflammation , interleukin 17 , dendritic cell , biology , chemistry , immune system , endocrinology
Human skin dendritic cells (sDCs) are potent Ag presenting cells that prime and bias naïve CD4 + T cells into Th1 or Th2 effector lymphocytes. Recent data demonstrated that human monocyte derived DCs secreting IL‐12 induced Th1 responses but abrogated a Th17 bias. However, it is unknown if human sDCs that do not secrete IL‐12 and promote Th1 differentiation by secretion of IL‐23 are also capable of initiating proinflammatory IL‐17 responses. Here we analyzed the stimulatory properties of sDCs regarding their ability to promote the differentiation of both Th1 and Th17 responses. DCs purified from cultures of human skin explants, stimulated the proliferation of naïve CD4 + T cells that differentiated into two distinct effector Th cell subsets secreting IFN‐γ and IL‐17 and which expressed the skin homing molecules CCR4 and CCR10. The Th1‐biasing function of sDCs relied on the production of IL‐23. Th17 responses depended on the combined effects of IL‐15 and stabilized IL‐6:IL‐6 Ab complexes that stimulated CD4 + T cells through a molecular mechanism involving IL‐6R trans‐signaling, an effect that was inhibited by specific blockade of the IL‐6R. Additionally, IL‐17 production was independent of IL‐23 and suppressed by TGF‐β. We conclude that human sDCs induce coexistent Th1 and Th17 effector T cells with potential to home to the skin which is relevant for the development of cutaneous inflammation and autoimmunity. Supported by NIH grants R01CA100893 to ATL and T32CA82084 fellowship to ARM.