Ligation of TLR9 induced on human IL-10–secreting Tregs by 1α,25-dihydroxyvitamin D3 abrogates regulatory function

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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2009-02, Vol.119 (2), p.387-398
Main Authors: Urry, Zoe, Xystrakis, Emmanuel, Richards, David F, McDonald, Joanne, Sattar, Zahid, Cousins, David J, Corrigan, Christopher J, Hickman, Emma, Brown, Zarin, Hawrylowicz, Catherine M
Format: Article
Language:English
Subjects:
Cancer
Cell receptors
Cellular signal transduction
Genetic aspects
Health aspects
Interleukin-10
Oncology, Experimental
Physiological aspects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.sup.+] 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.sup.+][CD25.sup.+] 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.sup.+][CD4.sup.+] 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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI32354