OX40 Ligand Shuts down IL-10-Producing Regulatory T Cells

IL-10-producing CD4⁺ type 1 regulatory T (Tr1) cells play a critical role in the maintenance of peripheral tolerance. Although immunosuppressive drugs, cytokines, costimulatory molecules, and immature dendritic cells are implicated in the induction of Tr1 cells, the signals that negatively regulate...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-08, Vol.103 (35), p.13138-13143
Main Authors: Ito, Tomoki, Wang, Yui-Hsi, Duramad, Omar, Hanabuchi, Shino, Perng, Olivia A., Gilliet, Michel, Qin, F. Xiao-Feng, Liu, Yong-Jun
Format: Article
Language:English
Subjects:
Antigens, CD
Biological Sciences
Cell Differentiation
Cell lines
Cells
Cells, Cultured
Cholecalciferol - pharmacology
Cholecalciferols
Cultured cells
Cytokines
Dendritic Cells - drug effects
Dexamethasone - pharmacology
Drug regulation
Drug therapy
Humans
Immunity (Disease)
Immunologic Memory - immunology
Inducible T-Cell Co-Stimulator Ligand
Interleukin-10 - biosynthesis
L cells
Ligands
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Molecules
OX40 Ligand
Proteins - metabolism
Stem cells
T cell receptors
T lymphocytes
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
Tumor Necrosis Factors - genetics
Tumor Necrosis Factors - metabolism
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Summary:IL-10-producing CD4⁺ type 1 regulatory T (Tr1) cells play a critical role in the maintenance of peripheral tolerance. Although immunosuppressive drugs, cytokines, costimulatory molecules, and immature dendritic cells are implicated in the induction of Tr1 cells, the signals that negatively regulate the generation and function of Tr1 cells have been elusive. We report that OX40 ligand (OX40L) completely inhibited the generation of IL-10-producing Tr1 cells from naïve and memory CD4⁺ T cells induced by the immunosuppressive drugs dexamethasone and vitamin D3. This unique function of OX40L was not shared by two costimulatory TNF family members, GITR ligand and 4-1BB ligand. OX40L strongly inhibited the generation of IL-10-producing Tr1 cells induced by two physiologic stimuli, the inducible costimulatory ligand and immature dendritic cells. In addition, OX40L strongly inhibited IL-10 production and suppressive function of differentiated IL-10-producing Tr1 cells. These two novel functions of OX40L shed light on the mechanism by which OX40/OX40L regulates immunity and tolerance.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0603107103