title: Ligation of TLR9 induced on human IL-10-secreting Tregs by 1alpha,25-dihydroxyvitamin D3 abrogates regulatory function.
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 1alpha,25-dihydroxyvitamin D3 (1alpha25VitD3), 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 1alpha25VitD3 in vitro. Furthermore, ingestion of calcitriol (1alpha25VitD3) 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 1alpha25VitD3-induced IL-10-secreting Treg with TLR9 agonists, CpG oligonucleotides, resulted in decreased IL-10 and IFN-gamma 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 1alpha25VitD3-induced IL-10-secreting Treg in vivo, and that this has implications in cancer therapy and vaccine design.
authors.affiliation: MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Urry
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Xystrakis
authors.forename: David F
authors.initials: DF
authors.lastname: Richards
authors.forename: Joanne
authors.initials: J
authors.lastname: McDonald
authors.forename: Zahid
authors.initials: Z
authors.lastname: Sattar
authors.forename: David J
authors.initials: DJ
authors.lastname: Cousins
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Corrigan
authors.forename: Emma
authors.initials: E
authors.lastname: Hickman
authors.forename: Zarin
authors.initials: Z
authors.lastname: Brown
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hawrylowicz
mesh_terms: D000328:Adult; D000368:Aged; D002117:Calcitriol / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000502:physiology*
chemical_list: C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D003907:Dexamethasone; D002117:Calcitriol