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.
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.
Barrat
Franck J
FJ
DNAX Research Institute, Department of Immunology, Palo Alto, CA 94304, USA. fbarrat@dvax.com
Cua
Daniel J
DJ
Boonstra
André
A
Richards
David F
DF
Crain
Chad
C
Savelkoul
Huub F
HF
de Waal-Malefyt
René
R
Coffman
Robert L
RL
Hawrylowicz
Catherine M
CM
O'Garra
Anne
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002762:Cholecalciferol / Q000494:pharmacology*; D016207:Cytokines / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018123:Receptors, Interleukin / Q000502:physiology; D053701:Receptors, Interleukin-10; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007166:Immunosuppressive Agents; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D014157:Transcription Factors; D016753:Interleukin-10; D002762:Cholecalciferol; D003907:Dexamethasone