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Cutting Edge: IL-27 Induces the Transcription Factor c-Maf, Cytokine IL-21, and the Costimulatory Receptor ICOS that Coordinately Act Together to Promote Differentiation of IL-10-Producing Tr1 Cells¹

Caroline Pot^*, Hulin Jin^*, Amit Awasthi^*, Sue Min Liu^*, Chen-Yen Lai, Rajat Madan^¶, Arlene H. Sharpe, Christopher L. Karp^¶, Shi-Chuen Miaw, I-Cheng Ho and Vijay K. Kuchroo^2,*

^* Center for Neurologic Diseases, Division of Rheumatology, Immunology, and Allergy and Department of Medicine, Brigham and Women’s Hospital, and Department of Pathology, Harvard Medical School, Boston, MA 02115; Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan; and ^¶ Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229

IL-27 has recently been identified as a differentiation factor for the generation of IL-10-producing regulatory type 1 (Tr1) T cells. However, how IL-27 induces the expansion of Tr1 cells has not been elucidated. In this study we demonstrate that IL-27 drives the expansion and differentiation of IL-10-producing murine Tr1 cells by inducing three key elements: the transcription factor c-Maf, the cytokine IL-21, and the costimulatory receptor ICOS. IL-27-driven c-Maf expression transactivates IL-21 production, which acts as an autocrine growth factor for the expansion and/or maintenance of IL-27-induced Tr1 cells. ICOS further promotes IL-27-driven Tr1 cells. Each of those elements is essential, because loss of c-Maf, IL-21-signaling, or ICOS decreases the frequency of IL-27-induced differentiation of IL-10-producing Tr1 cells.

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 a grant from the Swiss National Science Foundation (to C.P.), National Multiple Sclerosis Society Grant RG2571 (to V.K.K. and A.A.), National Institutes of Health (NIH) Grants R01 NS045937, R01 NS035685, R37 NS030843, R01 AI044880, P01 AI039671, and P01 NS038037 (to V.K.K.) and NIH Grant R37A138310 (to A.H.S.). V.K.K. is a recipient of the Javits Neuroscience Investigator Award from the NIH.

² Address correspondence and reprint requests to Dr. Vijay K. Kuchroo, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Harvard Institute of Medicine, Room 786, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: vkuchroo{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: Tr1, regulatory T cell type 1; Foxp3, Forkhead box P3; TFh, T follicular helper cell; WT, wild type.

⁴ The online version of this article contains supplemental material.

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