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 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.
Ito
Tomoki
T
Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, 77030-1903, USA.
Wang
Yui-Hsi
YH
Duramad
Omar
O
Hanabuchi
Shino
S
Perng
Olivia A
OA
Gilliet
Michel
M
Qin
F Xiao-Feng
FX
Liu
Yong-Jun
YJ
D015703:Antigens, CD; D002454:Cell Differentiation; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand; D016753:Interleukin-10 / Q000096:biosynthesis*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D053278:OX40 Ligand; D011506:Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D011506:Proteins; C478967:TNFSF18 protein, human; C089251:TNFSF4 protein, human; D048069:Tumor Necrosis Factors; D016753:Interleukin-10; D002762:Cholecalciferol; D003907:Dexamethasone