title: Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics.
abstract: TLR ligands are potent adjuvants and promote Th1 responses to coadministered Ags by inducing innate IL-12 production. We found that TLR ligands also promote the induction of IL-10-secreting regulatory T (Treg) cells through p38 MAPK-induced IL-10 production by dendritic cells (DC). Inhibition of p38 suppressed TLR-induced IL-10 and PGE(2) and enhanced IL-12 production in DC. Incubation of Ag-pulsed CpG-stimulated DC with a p38 inhibitor suppressed their ability to generate Treg cells, while enhancing induction of Th1 cells. In addition, inhibition of p38 enhanced the antitumor therapeutic efficacy of DC pulsed with Ag and CpG and this was associated with an enhanced frequency of IFN-gamma-secreting T cells and a reduction of Foxp3(+) Treg cells infiltrating the tumors. Furthermore, addition of a p38 inhibitor to a pertussis vaccine formulated with CpG enhanced its protective efficacy in a murine respiratory challenge model. These data demonstrate that the adjuvant activity of TLR agonists is compromised by coinduction of Treg cells, but this can be overcome by inhibiting p38 signaling in DC. Our findings suggest that p38 is an important therapeutic target and provides a mechanism to enhance the efficacy of TLR agonists as vaccine adjuvants and cancer immunotherapeutics.
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Jarnicki
authors.forename: Helen
authors.initials: H
authors.lastname: Conroy
authors.forename: Corinna
authors.initials: C
authors.lastname: Brereton
authors.forename: Graham
authors.initials: G
authors.lastname: Donnelly
authors.forename: Deirdre
authors.initials: D
authors.lastname: Toomey
authors.forename: Kevin
authors.initials: K
authors.lastname: Walsh
authors.forename: Cheryl
authors.initials: C
authors.lastname: Sweeney
authors.forename: Olive
authors.initials: O
authors.lastname: Leavy
authors.forename: Jean
authors.initials: J
authors.lastname: Fletcher
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
authors.forename: Padraic
authors.initials: P
authors.lastname: Dunne
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000378:metabolism / Q000637:transplantation*; D016219:Immunotherapy, Adoptive; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D008024:Ligands; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases