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Induction of IL-17⁺ T Cell Trafficking and Development by IFN-: Mechanism and Pathological Relevance in Psoriasis¹

Ilona Kryczek^2,*, Allen T. Bruce^2,, Johann E. Gudjonsson, Andrew Johnston, Abhishek Aphale, Linhua Vatan^*, Wojciech Szeliga^*, Yin Wang^*, Yan Liu^*, Theodore H. Welling^*, James T. Elder^3,,,,¶ and Weiping Zou^3,*

^* Department of Surgery, Department of Dermatology, Department of Radiation Oncology, Department of Microbiology and Immunology, University of Michigan Medical School, and ^¶ Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105

Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN- inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in humans. In this study, we demonstrate increased the number of CD4⁺ and CD8⁺ IL-17⁺ T cells in skin lesions of psoriasis. Furthermore, we show that myeloid APCs potently support induction of IL-17⁺ T cells, and that this activity is greatly increased in psoriasis. We tested stimuli that might account for this activity. Th1 cells and IFN- are increased in psoriatic blood and lesional skin. We show that IFN- programs myeloid APCs to induce human IL-17⁺ T cells via IL-1 and IL-23. IFN- also stimulates APC production of CCL20, supporting migration of IL-17⁺ T cells, and synergizes with IL-17 in the production of human β-defensin 2, an antimicrobial and chemotactic protein highly overexpressed by psoriatic keratinocytes. This study reveals a novel mechanistic interaction between Th1 and IL-17⁺ T cells, challenges the view that Th1 cells suppress Th17 development through IFN-, and suggests that Th1 and IL-17⁺ T cells may collaboratively contribute to human autoimmune diseases.

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 the Dermatology Foundation (to A.B. and J.E.G.), the National Psoriasis Foundation (to A.B.), the American Skin Association (to J.E.G.), Grant AR052889 from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (to J.T.E.), and Grant CA99985 from the National Cancer Institute (to W.Z.).

² I.K. and A.T.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Weiping Zou, Department of Surgery, University of Michigan Health Systems, 1150 West Medical Center Drive or Dr. James T. Elder, Department of Dermatology, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail addresses: wzou{at}med.umich.edu or jelder{at}med.umich.edu

⁴ Abbreviations used in this paper: siRNA, small interfering RNA; HBD, human β-defensin.

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