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Cutting Edge: OX40 Agonists Can Drive Regulatory T Cell Expansion if the Cytokine Milieu Is Right

Carl E. Ruby,^1* Melissa A. Yates,¹ Daniel Hirschhorn-Cymerman,^1¶ Peter Chlebeck, Jedd D. Wolchok,^¶||# Alan N. Houghton,^¶||# Halina Offner, and Andrew D. Weinberg^2*

^*Earle A Chiles Research Institute, Providence Portland Medical Center, Portland OR 97213; Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239; Department of Neurology and Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239; ^¶Memoral Sloan-Kettering Cancer Center, New York, NY, 10065; and ^||Wiell Medical College and ^#Graduate School of Medical Sciences of Cornell University, New York, NY, 10065

We report that OX40 stimulation drives all lineages of CD4 T cell development, including regulatory T cells (Tregs), and the plasticity of the response is dependant on local cytokines. In TGF-β1-treated cultures, an OX40 agonist increased IFN- and IL-4 production and diverted T cells from the Treg lineage. However, cytokine blockade in the context of OX40 stimulation promoted enhanced Treg accumulation. This observation was evident in naive mice, as OX40 engagement enhanced Treg proliferation and accumulation in vivo. Lastly, OX40 agonist administration influenced experimental autoimmune encephalomyelitis disease severity in opposing directions, depending on the timing of administration. Given during Ag priming, the OX40 agonist drove Treg expansion and inhibited disease, whereas given later it enhanced T cell effector cytokine production in the CNS and exacerbated disease. Hence, OX40 signaling can augment the accumulation of all CD4 T cell lineages; however, its accentuation of immune responses may have vastly different biologic outcomes depending upon the local cytokine milieu.

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 C.E.R., M.A.Y., and D.H.-C. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Andrew D. Weinberg, Earle A. Chiles Research Institute, Laboratory of Basic Immunology, 4805 Northeast Glisan Street, Portland, OR 97213. E-mail address: Andrew.Weinberg{at}providence.org

³ Abbreviations used in this paper: Treg, regulatory T cell; EAE, experimental autoimmune encephalomyelitis; eGFP, enhanced GFP; iTreg, inducible TGF-β1 Treg; LN, lymph node; PLP, proteolipid protein.