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1,25-Dihydroxyvitamin D₃ and IL-2 Combine to Inhibit T Cell Production of Inflammatory Cytokines and Promote Development of Regulatory T Cells Expressing CTLA-4 and FoxP3¹

Louisa E. Jeffery,^* Fiona Burke,^* Manuela Mura,^* Yong Zheng,^* Omar S. Qureshi,^* Martin Hewison, Lucy S. K. Walker,^* David A. Lammas,^* Karim Raza,^* and David M. Sansom^2*

^*Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom; and Department of Orthopedic Surgery, University of California Los Angeles Orthopedic Hospital, Los Angeles, CA 90095

The active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), has potent immunomodulatory properties that have promoted its potential use in the prevention and treatment of infectious disease and autoimmune conditions. A variety of immune cells, including macrophages, dendritic cells, and activated T cells express the intracellular vitamin D receptor and are responsive to 1,25(OH)₂D_3. Despite this, how 1,25(OH)₂D₃ regulates adaptive immunity remains unclear and may involve both direct and indirect effects on the proliferation and function of T cells. To further clarify this issue, we have assessed the effects of 1,25(OH)₂D₃ on human CD4⁺CD25^– T cells. We observed that stimulation of CD4⁺CD25^– T cells in the presence of 1,25(OH)₂D₃ inhibited production of proinflammatory cytokines including IFN- , IL-17, and IL-21 but did not substantially affect T cell division. In contrast to its inhibitory effects on inflammatory cytokines, 1,25(OH)₂D₃ stimulated expression of high levels of CTLA-4 as well as FoxP3, the latter requiring the presence of IL-2. T cells treated with 1,25(OH)₂D₃ could suppress proliferation of normally responsive T cells, indicating that they possessed characteristics of adaptive regulatory T cells. Our results suggest that 1,25(OH)₂D₃ and IL-2 have direct synergistic effects on activated T cells, acting as potent anti-inflammatory agents and physiologic inducers of adaptive regulatory T 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 M.H. is supported by National Institutes of Health Grant R01 2154380. L.E.J. is supported by The Arthritis Research Campaign. F.B. and M.M. were supported by Biotechnology and Biological Sciences Research Council Grant BBS/B/01014. O.S.Q. is supported by the Biotechnology and Biological Sciences Research Council and L.S.K.W. is a Medical Research Council Senior Research Fellow. Y.Z. was supported by the Medical Research Council.

² Address correspondence and reprint requests to Dr. David M. Sansom, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham B15 2TT, U.K. E-mail address: D.M.Sansom{at}bham.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T cell; T_FH, T follicular helper cell; DC, dendritic cell; 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; VDR, vitamin D receptor; MFI, mean fluorescence intensity.