Ligation of TLR9 induced on human IL-10–secreting Tregs by 1α,25-dihydroxyvitamin D3 abrogates regulatory function
Open Access
- 12 January 2009
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 119 (2), 387-398
- https://doi.org/10.1172/JCI32354
Abstract
Signaling through the TLR family of molecular pattern recognition receptors has been implicated in the induction of innate and adaptive immune responses. A role for TLR signaling in the maintenance and/or regulation of Treg function has been proposed, however its functional relevance remains unclear. Here we have shown that TLR9 is highly expressed by human Treg secreting the antiinflammatory cytokine IL-10 induced following stimulation of blood and tissue CD3+ T cells in the presence of 1α,25-dihydroxyvitamin D3 (1α25VitD3), the active form of Vitamin D, with or without the glucocorticoid dexamethasone. By contrast, TLR9 was not highly expressed by naturally occurring CD4+CD25+ Treg or by Th1 and Th2 effector cells. Induction of TLR9, but not other TLRs, was IL-10 dependent and primarily regulated by 1α25VitD3 in vitro. Furthermore, ingestion of calcitriol (1α25VitD3) by human volunteers led to an increase of both IL-10 and TLR9 expression by CD3+CD4+ T cells analyzed directly ex vivo. Stimulation of 1α25VitD3-induced IL-10–secreting Treg with TLR9 agonists, CpG oligonucleotides, resulted in decreased IL-10 and IFN-γ synthesis and a concurrent loss of regulatory function, but, unexpectedly, increased IL-4 synthesis. We therefore suggest that TLR9 could be used to monitor and potentially modulate the function of 1α25VitD3-induced IL-10–secreting Treg in vivo, and that this has implications in cancer therapy and vaccine design.Keywords
This publication has 65 references indexed in Scilit:
- Cooperation of Toll-like receptor signals in innate immune defenceNature Reviews Immunology, 2007
- How Toll-like receptors signal: what we know and what we don’t knowCurrent Opinion in Immunology, 2006
- Human CD4+ T Cells Express TLR5 and Its Ligand Flagellin Enhances the Suppressive Capacity and Expression of FOXP3 in CD4+CD25+ T Regulatory CellsPublished by The American Association of Immunologists ,2005
- Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-γ Production by Memory CD4+ T CellsPublished by The American Association of Immunologists ,2005
- Toll-Dependent Control Mechanisms of CD4 T Cell ActivationImmunity, 2004
- Toll-Like Receptor Ligands Directly Promote Activated CD4+ T Cell SurvivalThe Journal of Immunology, 2004
- TLR2 is expressed on activated T cells as a costimulatory receptorProceedings of the National Academy of Sciences, 2004
- Toll-Like ReceptorsAnnual Review of Immunology, 2003
- Quantitative Expression of Toll-Like Receptor 1–10 mRNA in Cellular Subsets of Human Peripheral Blood Mononuclear Cells and Sensitivity to CpG OligodeoxynucleotidesThe Journal of Immunology, 2002
- Tissue Expression of Human Toll-Like Receptors and Differential Regulation of Toll-Like Receptor mRNAs in Leukocytes in Response to Microbes, Their Products, and CytokinesThe Journal of Immunology, 2002