The Journal of Experimental Medicine
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Published 4 March 2002. doi:10.1084/jem.20011629
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© Rockefeller University Press, 0022-1007/2002/3/603/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 5, March 4, 2002 603-616

Original Article

In Vitro Generation of Interleukin 10–producing Regulatory CD4+ T Cells Is Induced by Immunosuppressive Drugs and Inhibited by T Helper Type 1 (Th1)– and Th2-inducing Cytokines

Franck J. Barrat1, Daniel J. Cua1, André Boonstra1,2, David F. Richards3, Chad Crain1, Huub F. Savelkoul2, René de Waal-Malefyt1, Robert L. Coffman1, Catherine M. Hawrylowicz3 and Anne O'Garra1

1 DNAX Research Institute, Department of Immunology, Palo Alto, CA 94304
2 Department of Immunology, Erasmus University Rotterdam, 3000 DR Rotterdam, Netherlands
3 Department of Respiratory/Medicine and Allergy, GKT School of Medicine, London SE1 9RT, United Kingdom

Address correspondence to Anne O'Garra, Division of Immunoregulation, NIMR, The Ridgeway, Mill Hill, London NW7 1AA, UK. Phone: 44-20-8959 3666 Ext. 2508; Fax: 44-20-8913 8528; E-mail: aogarra{at}nimr.mrc.ac.uk and Franck Barrat at his present address Dynavax Technologies, 717 Potter St., Suite 100, Berkeley, CA 94710. Phone: 510-665-7266; Fax: 510-848-5694; E-mail: fbarrat{at}dvax.com

We show that a combination of the immunosuppressive drugs, vitamin D3 and Dexamethasone, induced human and mouse naive CD4+ T cells to differentiate in vitro into regulatory T cells. In contrast to the previously described in vitro derived CD4+ T cells, these cells produced only interleukin (IL)-10, but no IL-5 and interferon (IFN)-{gamma}, and furthermore retained strong proliferative capacity. The development of these IL-10–producing cells was enhanced by neutralization of the T helper type 1 (Th1)- and Th2–inducing cytokines IL-4, IL-12, and IFN-{gamma}. These immunosuppressive drugs also induced the development of IL-10–producing T cells in the absence of antigen-presenting cells, with IL-10 acting as a positive autocrine factor for these T cells. Furthermore, nuclear factor (NF)-{kappa}B and activator protein (AP)-1 activities were inhibited in the IL-10–producing cells described here as well as key transcription factors involved in Th1 and Th2 subset differentiation. The regulatory function of these in vitro generated IL-10–producing T cells was demonstrated by their ability to prevent central nervous system inflammation, when targeted to the site of inflammation, and this function was shown to be IL-10 dependent. Generating homogeneous populations of IL-10–producing T cells in vitro will thus facilitate the use of regulatory T cells in immunotherapy.

Key Words: experimental autoimmune encephalomyelitis • vitamin D3 • Dexamethasone • T regulatory lymphocyte • autoimmunity


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