title: Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice.
abstract: Foxp3(+) regulatory T (Treg) cells can undergo reprogramming into a phenotype expressing proinflammatory cytokines. However, the biologic significance of this conversion remains unclear. We show that large numbers of Treg cells undergo rapid reprogramming into activated T helper cells after vaccination with antigen plus Toll-like receptor 9 (TLR-9) ligand. Helper activity from converted Treg cells proved essential during initial priming of CD8(+) T cells to a new cross-presented antigen. Help from Treg cells was dependent on CD40L, and (unlike help from conventional non-Treg CD4(+) cells) did not require preactivation or prior exposure to antigen. In hosts with established tumors, Treg cell reprogramming was suppressed by tumor-induced indoleamine 2,3-dioxygenase (IDO) and vaccination failed because of lack of help. Treg cell reprogramming, vaccine efficacy, and antitumor CD8(+) T cell responses were restored by pharmacologic inhibition of IDO. Reprogrammed Treg cells can thus participate as previously unrecognized drivers of certain early CD8(+) T cell responses.
authors.affiliation: Department of Pediatrics, Medical College of Georgia, Augusta, GA 30912, USA; Immunotherapy Center, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Madhav D
authors.initials: MD
authors.lastname: Sharma
authors.forename: De-Yan
authors.initials: DY
authors.lastname: Hou
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.forename: Pandelakis A
authors.initials: PA
authors.lastname: Koni
authors.forename: Yukai
authors.initials: Y
authors.lastname: He
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Chandler
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D045142:Cross-Priming / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000941:Antigens; C408982:CPG-oligonucleotide; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D014364:Tryptophan