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IL-23 Drives Pathogenic IL-17-Producing CD8⁺ T Cells¹

Bogoljub Ciric^2,3,*, Mohamed El-behi^3,*, Rosalyn Cabrera, Guang-Xian Zhang^* and Abdolmohamad Rostami^*

^* Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107; and Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905

IL-17-producing CD8⁺ T cells (Tc17) appear to play a role in a range of conditions, such as autoimmunity and cancer. Thus far, Tc17 cells have been only marginally studied, resulting in a paucity of data on their biology and function. We demonstrate that Tc17 and Th17 cells share similar developmental characteristics, including the previously unknown promoting effect of IL-21 on Tc17 cell differentiation and IL-23-dependent expression of IL-22. Both STAT1 and STAT4 are required for optimal development of Tc17 cells and maximal secretion of cytokines. Tc17 cells are cytotoxic, and they can be either pathogenic or nonpathogenic upon adoptive transfer in the model of autoimmune diabetes. Tc17 cells treated with TGF-β1 plus IL-6 are not diabetogenic, whereas IL-23-treated cells potently induce the disease. IL-17A and IL-17F are necessary but not sufficient for diabetes induction by Tc17 cells. Tc17 cells treated with TGF-β1 plus IL-6 or IL-23 likely differ in pathogenicity due to their disparate capacity to attract other immune cells and initiate inflammation.

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 from the National Multiple Sclerosis Society (to B.C.) and the National Institutes of Health (to A.M.R.).

² Address correspondence and reprint requests to Dr. Bogoljub Ciric, Department of Neurology, Thomas Jefferson University, 300 Jefferson Hospital for Neuroscience Building, 900 Walnut Street, Philadelphia, PA 19107. E-mail address: bxc170{at}jefferson.edu

³ B.C. and M.E.-b. contributed equally to this work.

⁴ Abbreviations used in this paper: ROR, retinoic acid-related orphan receptor; EAE, experimental autoimmune encephalomyelitis; T1D, type 1 diabetes; WT, wild type.

⁵ The online version of this article contains supplemental material.

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