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

• Published in: The Journal of experimental medicine 2002-03, Vol.195 (5), p.603-616
• Main Authors: Barrat, Franck J, Cua, Daniel J, Boonstra, André, Richards, David F, Crain, Chad, Savelkoul, Huub F, de Waal-Malefyt, René, Coffman, Robert L, Hawrylowicz, Catherine M, O'Garra, Anne
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antigen-Presenting Cells - physiology; CD4-Positive T-Lymphocytes - physiology; Cholecalciferol - pharmacology; Cytokines - physiology; Dexamethasone - pharmacology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Immunosuppressive Agents - pharmacology; Interleukin-10 - biosynthesis; Mice; Mice, Inbred BALB C; Original; Receptors, Interleukin - physiology; Receptors, Interleukin-10; Th1 Cells - physiology; Th2 Cells - physiology; Transcription Factors - physiology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20011629

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)-kappaB 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.