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Cutting Edge: An In Vivo Requirement for STAT3 Signaling in T_H17 Development and T_H17-Dependent Autoimmunity¹

Timothy J. Harris^*, Joseph F. Grosso^*, Hung-Rong Yen^*, Hong Xin, Marcin Kortylewski, Emilia Albesiano^*, Edward L. Hipkiss^*, Derese Getnet^*, Monica V. Goldberg^*, Charles H. Maris^*, Franck Housseau^*, Hua Yu, Drew M. Pardoll^* and Charles G. Drake^2,*

^* Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231; and Division of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91019

STAT3 activation has been observed in several autoimmune diseases, suggesting that STAT3-mediated pathways promote pathologic immune responses. We provide in vivo evidence that the fundamental role of STAT3 signaling in autoimmunity relates to its absolute requirement for generating T_H17 T cell responses. We show that STAT3 is a master regulator of this pathogenic T cell subtype, acting at multiple levels in vivo, including T_H17 T cell differentiation and cytokine production, as well as induction of RORt and the IL-23R. Neither naturally occurring T_H17 cells nor T_H17-dependent autoimmunity occurs when STAT3 is ablated in CD4 cells. Furthermore, ablation of STAT3 signaling in CD4 cells results in increased T_H1 responses, indicating that STAT3 signaling skews T_H responses away from the T_H1 pathway and toward the T_H17 pathway. Thus, STAT3 is a candidate target for T_H17-dependent autoimmune disease immunotherapy that could selectively inhibit pathogenic immune pathways.

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 National Institutes of Health grants and gifts from William and Betty Topercer, Dorothy Needle, and the Commonwealth Foundation. T.J.H. is a United Negro College Fund GlaxoSmithKline scholar. D.M.P. is a Januey scholar and holds the Seraph Chair in Oncology at Johns Hopkins University. C.G.D. is a Damon Runyon-Lilly Clinical Investigator.

² Address correspondence and reprint requests to Dr. Charles G. Drake, Department of Oncology, Bunting-Blaustein Cancer Research Building I Room 452, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, Baltimore, MD 21231. E-mail address: drakech{at}jhmi.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; HA, hemagglutinin; KO, knockout; T_REG, regulatory T cell; WT, wild type.

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