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

By F. Barrat, D. Cua, A. Boonstra, D. Richards, C. Crain, H. Savelkoul, R. de Waal‐Malefyt, R. Coffman, C. Hawrylowicz, A. O’Garra. Journal of Experimental Medicine, 2002

1,259 citations recorded by the source corpus.

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)-γ, 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-γ. 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)-κB 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.

Subfields: Immunology

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In Immunology

1. A. O’Garra
2. Yong‐jun Liu
3. A. Krieg
4. C. Hawrylowicz
5. P. Vieira
6. M. Saraiva
7. B. Blazar
8. A. J. Dawson

Citations in the corpus

• The regulation of IL-10 production by immune cells (2010, background): “However, IL-10 enhances the differentiation of IL-10-secreting T Reg cells, thus providing a positive regulatory loop for its inductio”
• Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. (2005, background): “IL-5, IL-10, IL-13, and IFN-γ were measured using ELISA and matched antibody pairs (BD Biosciences — Pharmingen), with reference to commercial standards (R&D Systems).”
• Pharmacokinetics and Pharmacodynamics of Systemically Administered Glucocorticoids (2005, background): “[193,194] glucocorticoids might induce differentiation of Th0 Glucocorticoids can induce apoptosis by several to Treg1 cells.[185,186] Up-regulation of TGFβ recep- mechanisms.”
• Foxp3 Expressing CD4+CD25high Regulatory T Cells Are Overrepresented in Human Metastatic Melanoma Lymph Nodes and Inhibit the Function of Infiltrating T Cells1 (2004, background): “T cells under defined conditions of Ag stimulation in the presence of immunosuppressive drugs or cytokines (28, 58, 59).”
• Human Plasmacytoid Dendritic Cells Activated by CpG Oligodeoxynucleotides Induce the Generation of CD4+CD25+ Regulatory T Cells1 (2004, background): “, IL-10, TGF- ) (30–32), stimulation with immature myeloid DCs (33–35), or immunomodulatory drugs such as vitamin D3 (36).”