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Differential Capability of Human Cutaneous Dendritic Cell Subsets to Initiate Th17 Responses¹

Alicia R. Mathers^*,, Brian M. Janelsins^*,, Joseph P. Rubin, Olga A. Tkacheva^*, William J. Shufesky^,¶, Simon C. Watkins^,,||, Adrian E. Morelli^,,¶ and Adriana T. Larregina^2,*,

^* Department of Dermatology, Department of Surgery, Department of Cell Biology and Physiology, Department of Immunology, ^¶ T. E. Starzl Transplantation Institute, and ^|| Center for Biological Imaging, University of Pittsburgh Medical Center, Pittsburgh, PA 15213

Human skin-migratory dendritic cells (DCs) have the ability to prime and bias Th1 and Th2 CD4⁺ T lymphocytes. However, whether human cutaneous DCs are capable of initiating proinflammatory Th17 responses remains undetermined. We report that skin-migratory DCs stimulate allogeneic naive CD4⁺ T cells that differentiate simultaneously into two distinct effector Th17 and Th1 populations capable of homing to the skin, where they induce severe cutaneous damage. Skin-migratory Langerhans cells (smiLCs) were the main cutaneous DC subset capable of inducing Th17 responses dependent on the combined effects of IL-15 and stabilized IL-6, which resulted in IL-6 trans-signaling of naive CD4⁺ T cells. Different from smiLCs, purified skin-migratory dermal DCs did not synthesize IL-15 and were unable to bias Th17 responses. Nevertheless, these dermal DCs were capable of differentiating Th17 cells in mixed leukocyte cultures supplemented with IL-15 and stabilized IL-6. Overall, our data demonstrate that human epidermal smiLCs induce Th17 responses by mechanisms different from those previously described and highlight the need to target clinical treatments based on these variations.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants R01 CA100893 (to A.T.L.), T32CA82084 fellowship (to A.R.M.), R01 HL075512, and R01 HL077545 (to A.E.M.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Adriana T. Larregina, Department of Dermatology, Lothrop Hall Suite 145, University of Pittsburgh Medical Center, 190 Lothrop Street, Pittsburgh, PA 15213. E-mail address: adrianal{at}pitt.edu

³ Abbreviations used in this paper: DC, dendritic cell; smiDC, skin-migratory DC; DDC, dermal DC; smiDDC, skin-migratory DDC; LC, Langerhans cell; smiLC, skin-migratory LC.

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